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Dissertation planning gain supplement capstone counseling in richmond va dispute equifax business report ´╗┐good morning how wonderful to see you all here at the annual holiday lecture series this was originated over fifty two years ago by one of our late and fantastic professors I'm glad to see the turnout it's fortunately not with 30 inches of snow which it sometimes is I'm introducing a very special lecture highlighting and marking the incredible work of a very close friend Ralph Steinman rau Steinman and I knew each other for over 40 years here at the Rockefeller University Ralph and I are both physician scientists and professors and heads of laboratories you're going to hear a great deal about the phenomenal work of his laboratory and I'll simply say my laboratory bears the title it always has the laboratory of the biology of addictive diseases on October 3 while I was on a plane to Stockholm two things were announced Ralph had just won the Nobel Prize the greatest prize awarded to a scientist International Prize coveted coveted by all won by and very few and very deservedly I also learned that he had passed away three days before it was a bit of a tough ride but I went with a pride and the love of Ralph and his family and all of his workers today's lectures will highlight the work that was awarded the nobel prize that is Ralph's work in a discovery of dendritic cells a very special cell type which he found and which he went on to study for the development of medications and vaccines to treat a variety of disorder and protect against some including hiv/aids and a variety of forms of cancer today they'll be two lectures one in the morning and one in the afternoon from two leaders from Ralph's laboratory we're going to hear how he first discovered the cells in 1972 by simply looking into a microscope how many of you have looked into a microscope well keep your eyes open when you look into the microscope you may see something you didn't expect to see and don't think you're wrong just keep looking at it because what Ralph found was very unusual and he realized what these cells were which is different and then to find what they were which is very special it's a wonderful story and it will be written for years to come as scientists around the world are working based on his findings to make medications and vaccines for a variety of diseases SOT Jim can you progress I can't progress it's not progressing oh good so this is 1992 we had known each other for about 20 years at that time and this is the picture the annual picture of the hospital and it was a windy day but Ralph and I frequently would stand together in pictures because we remember from the seventies to really the mid 80s no one believed that he had really found a new kind of cell and no one really believed all the wonderful things that did it was slow it was coming but bit by bit different wonderful immunologists learned no one believed that I had really defined that addictions alcoholism cocaine addiction nicotine addiction are diseases of the brain and not some personality trait disorder and that medications coupled with behavioral care can make people well and we have shown this now with a million people in methadone maintenance treatment worldwide which we developed here but we kind of bonded closely because we were doing different things and having different laboratory groups Ralph was ultimately not only believed but followed by the majority of immunologists in the world if not all and many of us beyond although he is no longer with us his legacy will go on forever - Sara session jure I will brag she went to the same college I went to a tiny college a women's college Wellesley and she went on as I did to go to medical school at rush and then she went on to be chief resident and pathology across the street at New York Cornell York Presbyterian Weill Cornell call today and then she went down and worked with the Armed Forces Institute of Pathology and she worked on developing an AIDS vaccine she was at Walter Reed in its original site and now I'm sure visits in this beautiful new site and she worked both in Bethesda and in Washington but around the world with her development of AIDS vaccine and then having worked here at Rockefeller from the age 17 onward while a student hint-hint I worked at the NIH for a student in high school and college she then returned here to Ralph's lab in 2003 and has played a marvelous role with Ralph as a friend a colleague and heading up his clinical research vaccine team slide please Rena Kowski is she had a new generation of physician scientists and she was a clinical scholar here after having graduated from a university in Brazil she went to the federal university of ser Griffith I hope I pronounced that almost right and then came to New York to do our house staff residency at st. Luke's Roosevelt which is affiliated with Columbia PMF and then she came to be a clinical scholar here at Rockefeller a fantastic program connected with our hospital here in our clinic where Ralph and I did and I still active present do very very constant and exciting research and she has joined the laboratory of Ralph Sarah is an associate professor of Clinical Investigation and Marina is very recently now an assistant professor of Clinical Investigation so we have a litany of women as well as been at this university doing science and in our cases as physician scientists I would also like to acknowledge ruffs family this is Claudia his wife in a front row receiving the Nobel Prize on December 10 from the king of Sweden at town hall a beautiful beautiful place and she is receiving it I hope you'll get to see some more of the pictures another time with much of the family in attendance and Michele listen swag one of his most outstanding trainees had given the Nobel lecture just before on a previous day so this is the story of the Rockefeller University our connectivity with each other our closeness our family here at the Rockefeller University and with no further to do I'm going to turn the lecture over to one of my close friends and colleagues Sarah Schlesinger [Applause] so good morning everybody I am delighted to be here and I'm delighted that you're here so we are here for an hour and a half now we'll have lunch which is pizza for those of you who like to look forward to lunch and then Marina will take this take the podium in the afternoon to tell you the rest of the story so as Mary Jean told you I'm going to tell you about Ralph's amazing discovery of dendritic cells and the marina is going to tell you about some of our more recent work which is more clinically applied but we're going to be sitting here for a long time and I'm so delighted to see so many of you taking a day of your precious Christmas vacation or holiday vacation to join us to explore science um but you guys can't sit there or you'll fall asleep and you'll miss miss the fun so what I'd like is I'd like for you to ask questions there are two microphones I think we're where the microphones over there and over there this is webcast so even if I can hear you people who are watching on the webcast won't be able to hear you unless you use one of the microphones so any time if you have a question please ask it I will be asking you questions and there is an incentive for both asking and answering questions and that is my little Carol Carol Merrill moment these are little stuffed dendritic cells and these are pathogens okay a whole bunch of different germs each one cooler than the next so if you ask or answer a question you can come and get one of these I would throw unto you but I've got a really bad throwing arm and it probably wouldn't get to you so these are really cool and my favorite one of these that's the Black Plague thank you this is a superbug okay this is staffed Staphylococcus aureus which is grows in clusters and it's a super bug as it as a superhero cape so if I asked a good question that's the one I'd go for so feel free at any time to interrupt and ask a question and you two can have a super bug so as as Mary Jean told you we are here today for a remarkable reason and that is to celebrate and to learn about the work that led to the awarding of the 2011 Nobel Prize in Physiology or medicine and the citation for the prize read for his discovery of the dendritic cell and its role in adaptive immunity and I put here this is what the the Nobel award actually looks like and also as Mary Jean told you sadly Ralph died three days before he was able to even learn that he'd received the prize and he certainly wasn't able to attend the ceremony in Sweden on December 10th but his lovely wife Claudia received the prize in his stead and here you see her receiving it right there from the king of Sweden and Claudia is here today with two of Ralph's children and two of his granddaughter's ladies could you come up and show everybody so this is so this is you want to say your name or should I say it rain ah ha and who's this this is sila and they are getting ready like you guys to be scientists so they're here too and they'll help us through some of the stuff okay don't you want to if I can sit down [Applause] okay now I am here as Mary Jean told you because I've worked with Ralph for virtually all of my professional life in one way or another and my professional life started when I was 17 even though I didn't realize it at the time but I'm uniquely qualified to be giving this lecture because 35 years ago I was in the audience so I am NOT a hoarder but I managed to keep both this little letter and I'll show you my ticket that I was sent 35 years ago and this only kind of shows how things have changed the stationery is a little simpler we have a different zip code and this was actually typed on a typewriter and signed by hand and if it says here Ms Lewis says feel free to call me and this number with no area code between the hours of 9:00 and 2:00 Monday through Friday because that was the only way to reach her there was no cell phone and if you called you wouldn't get voicemail so things have changed a bit these were also the Alfred E mirskiy Christmas lectures on science is opposed to the holiday lectures and I just wanted to say a word about Alfred mirskiy for whom the lectures were named he was a scientist here at the Rockefeller who believed you got people into science by hooking them early and I think it works it worked for me and I hope it will work for you so this was my ticket they only they were perforated tickets then they only took the first lecture and there were two days of lectures and they were only in the afternoon but I had the great pleasure and and really it was a life-changing experience for me to hear dr. Christian de Duve lecture on a guided tour of the living cell this was 1976 and he had won the Nobel Prize in 1974 for his work describing the micro anatomy of the cell with Georg Pilate and you'll hear a little bit more about that later but it was a remarkable and inspiring experience for me not just to hear about his discoveries but to hear about how he did it and so that's what we're going to try to tell you today to teach you a little bit about what Ralph discovered but perhaps more importantly how he did it because that's really the fun and most interesting part hmm oh so this is dr. de Duve and he was and so in 1974 he was at the peak of his sort of academic powers and he's in his mid 90s I think he's 95 or 96 now and he's still working and I had the great privilege of sitting with him was one of my good friend and colleagues here jackie Chiappetta her her sister Adelaide works with him and arranged for me to meet him and the lecture that he gave is actually published in a wonderful Scientific American book and he gave it to me which I didn't even know so if you are interested you can you can to have a guided tour through the cell and this is my ID part from 1979 I couldn't find the one from 77 or 78 but we had to blur out the social security number which appeared on it it was laminated it had no electronic capabilities my ID card now gets me into all sorts of doors and stuff but it didn't have my picture which I don't look like anymore so and this is the last of my reminiscences this is a picture of our lab from 1980 to 81 and this picture actually hangs on the wall currently and I don't know if you can find me or find Ralph but we'll help you do that so here I am again looking quite a bit different and there Ralph is looking pretty much the way he always did so I got to work for Ralph through a series of very unusual totally random coincidences I came home from the lecture and told my parents we had never heard of this institution I don't know how many of you had heard of the Rockefeller before you came here but I hadn't and I said it looked like it would be a really good place to have a summer job so my parents said that's fine with us if you want to and my mother knew somebody who new Claudia Ralph's wife and I got Ralph's phone number and I just called him now fortunately or unfortunately things are more organized now and I don't suggest that you randomly call or email people but we have a program for high school students who are interested and it's called the Rockefeller University science research program or the outreach program and if you go to our website in Google you'll find it and there's an online application and I highly recommend the program it's run by Ted Scoville and it's a terrific way to come here and and really learn science by doing science so this is Ralph on his first day of physical diagnosis at Harvard Medical School I guess he did look different then and that was 1964 so Ralph as Mary Jean mentioned we are all physician scientists so there are people who are have MDS and there are people who have PhDs and we are scientists with as I like to say only an MD degree they're both paths are good both paths give you lots of opportunity but being a physician scientist is a little bit different and Ralph spent most of his life in the beginning working as a basic scientist and then in the last decade or so he began to he took his discoveries and he applied them to medically important problems in a more directed way so you're gonna hear about both phases of his career and in valves office he had on a white board and you know a white board that you write on and on that white board were many quotations and so obviously and it would be silly of me not to mention this we would all prefer that he were here to give this lecture you would be preferred you would prefer to be hearing it from a Nobel Prize winner himself we all wish he were here and believe me me most of all would rather be sitting in the audience and listening than being up here though it is obviously a great honor and a great privilege for me to be here but I want to give you if as best I can some sense of Ralph's some sense of his enthusiasm his pleasure in science and and and how much fun he thought it was so throughout the lecture are a few little quotes some of which he had up on his whiteboard and some of which he sent me in an email when I asked him for this one to include an Electra I was giving also he had a way of collecting objects that looked like dendritic cells so they had nothing to do with them but they just reminded him so you're gonna see images of some of those objects through the talk as well so this this my French is really crummy and my accent is horrible it was always a great comfort because even though Ralph's French was fluent his accent was worse he'd grown up in connect and French French speaking francophone Canada so I'm just gonna go for the English which is chance favors the prepared mind but this is the lowest or quote and he gave it in a lecture in 1854 so I think that there's a lot of truth to that and it applied to Ralph in the end any discovery hinges on a certain amount of luck and a certain amount of magic but he was extremely well prepared and that's what you can do you can prepare yourself you can train yourself and then when it happens you can avail yourself of the luck so this is one of the images that I'm going to show you and these are glass objects that were made if you are interested in Venice by a mr. Gulati who never knew about dendritic cells but they've become dendritic cells for us science has been important for me when I was in college when I entered college I have a focus in terms of what I was interested in professionally but that is when I took my first course in biology and then I was hooked nothing else when did you first sort of set your sights on looking at dendritic cells when I began my postdoctoral research what I was really trying to do is understand a problem in immunology and medicine the problem was how do you start your immune reaction so the immune system is very important in many diseases but we didn't understand how the whole thing gets going so if there's an infection and your immune system has to respond how do those two come together how is the response initiated and we were looking in a very simple contrived experimental system which was the only one I could identify to study this problem and we found this totally new cell I couldn't have anticipated it was brand new but we were so sure this was a new entity that it was really relatively straightforward to persevere now everything he said was absolutely true except the very last thing it wasn't relatively straightforward to persevere and one of the things that made Ralph so different from for most other people most other scientists was his perseverance his willingness to stick with what his observations were so as Mary Jean Creek told you and is in actually in the title of this this was a very controversial discovery and he discovered the cells in 1972 and it really took 10 to 15 years before they were accepted by the rest of the community and during that time Ralph's work really is probably the only person or his group worked as the only group working on dendritic cells and it was straightforward for him because once he saw it and he knew it that was it but for the rest of the world it wasn't so straightforward so now I'll catch up her cell and so to understand what Ralph's discovery meant and how he discovered the cells that he did you need to know a little bit about immunology and what was understood at the time so immunology really began as a discipline in nineteen oh it was recognized as his discipline in 1908 with the Nobel Prize being awarded to Paul Ehrlich for adaptive immunity and he discovered antibody he called it side chains but he discovered the idea of antibody and we've provided for you a handout that that kind of goes over all this so I don't think you have to take too many notes if you're any at all because you have it all there so you don't have to take notes but anyway and this is ela Ilya menshikov who discovered innate immunity he discovered phagocytes so the cells that we work on are part of the family of phagocytes and their cells that eat up other cells or other debris and dendritic cells linked the two parts of the immune system the innate which happens immediately and the adaptive which takes a little longer and is characterized by memory so in metchnikoff Snowbell lecture he said there's no need to be a doctor or scientists to wonder why the human body is capable of resisting so many harmful agents in the course of everyday life so if you think about it we live in a world full of danger a world full of foreign material and how is it that with all of those pathogens over there that we all manage so it was understood from very early on that people who were infected by the plague of Athens who recovered didn't get it again so the idea that natural infection would protect you from subsequent infection goes back to the ancient world but nobody understood or or had any reasonable approach understanding how that happened Jenner who you'll hear more about from marina in the afternoon lecture made observations about milkmaids who are protected from smallpox by a different infection by cow pox and he capitalized on that observation to make effect to make smallpox vaccine which is actually the only vaccine that's responsible for eradicating a pathogen from from human disease so the smallpox vaccine has successfully eradicated smallpox but again he didn't understand why so those observations are pretty clear and here we have a person in all of the various pathogens that you're encountering or when it's encountering every day and it's our immune system that protects us so this is I love this this is our mute forgive me this is our immune system okay so you have different cells you have phagocytes you have lymphocytes you have granulocytes all of them working hard to protect you we defend so the essential elements in immunity and forgive me for those of you who know this already just bear with me because we need to make sure that everybody's on the same page if anybody has any questions and it's not clear please ask so the essential elements in an immunity the first is an antigen so an antigen is any substance either foreign or self that is recognized by the immune system so that could be any of the microbes pollen or an allergy or vaccines when we intentionally manipulate the immune system and Ehrlich described side chains which have subsequently been learned we learned our antibody and that's a protein in the blood that's made by b-cell lymphoma siz known as the humoral arm of the immune system sometimes these are called antisera cellular immunity which is what we work on are this response of direct response of cells in the immune system that directly respond to an antigen so this is another little cartoon of my friends here showing you how the immune system works and the the key thing to remember about the immune system are these properties the first is it's specific so you make a specific response to a specific microbe or a specific allergen it's not general so if you respond to the common cold that doesn't cross to chickenpox then the next character the next property is its diverse you make many many responses hundreds or thousands to any given antigen and perhaps most importantly is that the immune system is characterized by memory so this is sometimes called amnestic and what that means is when the immune system learns when you first encounter an immunogen or a pathogen you make a response and ever after that the eat the immune system remembers and mounts a faster quicker more intense response upon reach allenge so specificity diversity and memory and the the constituents of the immune system and these are the constituents as they were understood in the early 70s and and this remains correct I'm not going to give you any misinformation and where things divert diverge from what was understood I'm going to tell you so these are b-cell lymphoma D or the humoral arm of the immune system and the B people sometimes think it stands for bone marrow because they come from the bone marrow but these were first described in birds and birds have a common immune organ called the bursa or the bursa of Fabricius and they're actually called B syllabus sites for that origin and they produced immunoglobulin or ant or antibody in response to antigen and this is a cartoon of the b-cells and so you have antigen a young or immature b-cell and it is it receives help and this is very important from an activated t cell which you'll hear about in a moment it grows up to be a plasma cell and it pours out as ralph would say buckets and buckets of antibody and you see here you're gonna see better in a moment the shape of the antibody is a Y shape so antibody or immunoglobulin is produced by b-cells and it may be neutralizing which means it kills a bacteria or a virus or non neutralizing and just binding and this is what it looks like Gerald Adelman who was here in the 70s was awarded the Nobel Prize for describing this so you have this portion which is the variable region and this is what's different for each antigen and this is the common region or the FC region the constant region and this remains the same and here you have a light chain and a heavy chain and there are two different versions of light chains and the variability as I said is all in this end or the antibody binding region sometimes called the FA B region t-cell lymphocytes and these were you know for us these are sort of dogma but these were described in the 60s so when ralph was working the description of t-cell lymphocytes and the characterization of them was relatively new their effector cells and they come from the thymus hence the t-cell the thymus is an immune organ that we all have it sits over the heart and it's the largest it ever is in when you're 2 years old so it's pretty large when you're born it grows too you're 2 years old and then an involute so if you know any 2 year olds they've got good thymus it's a cd4 cells or T cells or helper cells those are the cells that make the help that you saw helping to make antibody and then see the eight cells are T cells that are killer cells and they directly kill by con contact and they are critical and antiviral and anti-social lymphocytes T cells B cells cd4 and cd8 when you look at them in the microscope there's no way to tell them apart they look like little bland round cells they have different molecules on their surface which is how we stain them to characterize them but they're all there mimics for each other.when and this is a resting helper t-cell and this is a resting cytotoxic t-cell when a t-cell resting when a helper t-cell becomes activated it pours out cytokines particularly il-2 and then when arresting cytotoxic T cell becomes activated it it directly kills and it does so by secreting again directly perforin and granzymes so perforin as you might guess from the name of it makes holes in another cell and kills that way and grants i'm is equally toxic sure so i realize that is characterized by memory but then why do you need to get booster vaccines when you've already gotten a vaccine that's a very good question and the reason is because it's imperfect so when you get when you get sick when you get say let's take smallpox which is the best example I can think of if you get natural infection with smallpox 70% of people who get infected are going to survive and 30% are gonna die if you're in the lucky 70% who live you don't need to get boosted ever again you have lifelong durable immunity but the vaccine is a mimic of the natural infection and it isn't quite as good one of the goals in fact in developing vaccines is to make vaccines that only need to be given once because it's a pain it's a pain in the neck for you to go back to your doctor to get a booster but if you're in in what in West Africa and you have to go out into remote villages the people it's a matter of life and death whether you can protect people long-term so it's it's it's due to the imperfection in our technology and not the imperfection of the immune system because a good robust natural infection will give you durable immunity you get to come down and pick a bug [Applause] good question and thank you for asking can I get the Black Death you can get the Black Death that is the Black Death one of my very favorites alrighty so when we so we're always looking for vaccines that are durable and don't require boosting and one of the things that you're going to hear about in the afternoon is Ralph's had a great idea that we're working on for making vaccines that are more durable and if you think you need a lot of boosters with the shots that we get now with the current there's a current AIDS vaccine that's been tried that shows the ability to protect which is wonderful but it only lasts for about six months so terrific that it works but from a practical point of view you've got to vaccinate people every six months you don't have a product you have a science experiment so this is an le spot so this is a way of measuring the the remember I told you cd8 cells secrete various substances which kill directly and you can't see them but this is a way we detect them in the laboratory using an le spot so in Eliza technology in spots and each of those spots represents a cell that's making interferon gamma which is the cytokine that we were looking for once again one of the beautiful venetian glass dendritic cells I would have liked to have been able to distribute them but we didn't have the budget so when Ralph came he knew about t-cells and b-cells and immunity and as he told you in his little little video that I managed to almost miss that what interested him this is really creepy was the question of how the immune response gets started so how do you initiate immunity and nobody really knew that there was some sort of vague understanding that there were accessory cells involved but it wasn't clear and very often when something isn't clear it's because we don't know enough so Ralph came to work with doctors envel Cohen who was his mentor um you I had the great privilege of working under for several for many years who was a wonderful wonderful man and if dr. Cohen had lived he would have no doubt shared the Nobel Prize with Ralph to the discovery of dendritic cells because they worked closely together and it was sans insight and support that allowed Ralph to continue working on something for 16 or 18 years when really very few other people but the two of them believed that it was the case and he was also a really nice man as was Ralph this is dr. Cohen and if the time Ralph came to the lab he shared the lab with dr. Hirsch and they worked on macrophages which were the primary phagocytes in which people were interested at the time and the lab had been headed previously by dr. Rene DuBose who was a soil microbiologist and dr. Bhutta Bose discovered the first antimicrobial anti-tuberculosis and so he was interested in tuberculosis and tuberculosis grows in macrophages so dr. Cohen had come to work with him on the macrophages that were the relevant cell for the pathogen that he worked on and deep in there there is a tuberculosis term so now again we turned to a system in which immunologists would take two sources of cells to generate an immune response on the one hand they took cells that are called lymphocytes that mediate the immune response the fact that was discovered by Sir James gallons in England about ten years before I started my work and then they would take another cell population that's stuck to a glass or tissue culture surface and by mixing the two of them together they then could have an antigen or stimulus and get an immune response so I decided I would look at these adherent or sticky cells to see what their properties were to try to understand how you initiate an immune response now when I look down the microscope I saw some that was totally so we turned to a system in which totally surprising there we go okay and this is the microscope that he looked down so this is our new laboratory but Ralph worked and when you come out here when you come out the front if you look to the right there's a gray building which is called the Bronk lab and actually when Ralph came here it was called the south laboratory and he worked there for 40 years last August not this past room but the one before we moved to the new lab right across the way from here but this microscope was with Ralph in the beginning and it went with him everywhere and this was the scope in which he looked down and saw the cells and it wasn't just that he saw them but he recognized them and this is his handwriting he labeled it because people tended to take stuff still dude and that's I guess it'll now be preserved for history so as ralph said when if he he was interested in figuring out how the immune response was started what generated immunity and the system that he worked with was to take take B cells and T cells and mix them together and add an accessory cell so the accessory cell was one that stuck to glass and remember there were no monoclonal antibodies to characterize cells so you couldn't say this is a T cell this is a B so everything was separated by physical properties and then they were mixed together and you would look for an antigen specific antibody response or plaque forming cells don't be sorry that's how to do with the immune system and how it remembers your responses to everything basically uh-huh so if it does remember then how do we get the cold so often is it like a different strain or exactly so for that you get a cold virus I also had a question like what like uh-huh okay what makes the cold so different like why is it evolving so often why is so you're you're absolutely on the right track the reason that you can get a cold over and over again is actually twofold one is a cold refers to a clinical syndrome so there are many different viruses that can give you something that feels like a cold but if it's the Rhino virus which is the actual cold as opposed to say ad no virus or enterovirus because there are many different viruses that can give you a similar clinical syndrome it mutates very rapidly it's the same problem as influenza so you make everybody here I bet has a robust response to influenza whether you've been vaccinated or not but that doesn't mean that you don't need to get the flu shot because influenza mutates it's such a rapid rate that the virus that's circulating now is sufficiently different from the one to which you made an immune response that you won't be protected so there's what's called homologous protection and heterologous protection so homologous protection is being protected from the same thing to which you made the response and I guarantee you if you got exposed to the same cold virus you wouldn't get it again but it's that the virus is mutated sufficiently to no longer be what's called a homologous challenge you're welcome you cannot rely on my throwing abilities they're worse than my Av abilities all right so he oh it's not I don't know though if it'll be pretty it will be do you might just just walk walk over there okay whoa wait I'll get my microbes ready come if you've got a question come up Goku yeah but but I want to hear it but just go stand at the microphone so everybody else can hear - hello okay that one's working hi great so my question lies with actually your present slide uh-huh I understand who you were talking about isolating I mean will rather separating the B cells and the T cells based on physical properties but how did I mean whoever did this how did they know to isolate the B and T cells in the first place okay so they didn't so that's a very good question because that clarifies what I said which is wrong they didn't isolate the beat cells and T cells they were a mixture of lymphocytes so what they put in with the cells that they could see as lymphocytes and these are all coming from Mouse spleens and they looked the same but they had a mixture of eh sales and T cells it's only later that they would separate them okay so for that I think you get a white cell these here no no you can't rely on me to throw come all the way down okay next question yeah my question is pretty short that's fine what substance that ruff used to they identify these dendritic cells what substance has eyes that's but but that's really yeah well what happened oh okay so that's a that's a very fair question III he started with Mouse spleen cells and actually I'm gonna get to that you're gonna see them in just a minute but he start so all of these cells the B cells the T cells the macrophages and the dendritic cells weren't isolated from the splenocytes of mice so mice are a very good experimental system because they're like us in a lot of ways they're not like us in every way they're not perfect but they work pretty well and the spleen which is an immune organ which we have in people there's a lot of connective tissue in it so it's hard to get the cells out but in mice it's basically it there's very little connective tissue and the cells come out easily so it was a system that a lot of people worked on including these that Michelle and Dutton and it was where Ralph started so it later on you're gonna hear about dendritic cells from human blood and dendritic cells from human skin but this part is all Mouse splenocytes so and I'm going to we're going to talk about how he separated them so if you hold on you'll hear about it and if it's not clear come back and ask but the most important thing that I want you all to understand is he saw the cells there was no fancy chemistry there was no fancy PCR PCR didn't exist but it was good observation it was looking to see what was before him and not what he expected to see that led him to this discovery and that's the if you come away with one lesson that's what I'd like you to learn you can come down and get a bite a white tail or a pathogen whatever you like okay you can pick that's my favorite one that's it that's the superbug so show hold that one up okay so that's Staphylococcus aureus which grows in clusters so it's like a little cluster but it's a superbug and it has a superhero cape on it so I think that's the best one it's alright as many as many questions as you have alright so the first question is I guess like you know when you get your tetanus vaccine AHA you're immune for 10 years does the immunity period very like by how like well the vaccine mimics so you're not immune for 10 years nobody wants to figure find how long you're immune for because if they found how long you're immune you would get infected what's known is if you're boosted every 10 years you maintain your immunity so tetanus is a really good example because you can measure neutralizing antibody so remember when we talked about antibody back a few slides there's neutralizing and non neutralizing with tetanus you get neutralizing antibody so what's known is that and you have to look in populations there are people who can probably get a tetanus shot and be protected forever with one shot and there but everybody is protected or virtually everybody if you re immunize every ten years so that's one of the things that's really interesting about vaccinology is that you have these issues of cellular immunity but then there are these big issues of public health and so even if you aren't even if you don't need to be revaccinated if your vaccine is good for twenty as long as somebody in the population needs it every ten years the recommendation has to be every ten years vaccines like the HPV cervical cancer type uh-huh protection you have to get three of those every six you have to get three one every six months and then after the third shot you're protected I guess for life right well that's actually a very good question that's a new vaccine so the HPV vaccine which is a wonderful vaccine it was invented by people who colleagues of ours who we know and like and it works really well and I would strongly recommend to everyone of you male or female in the audience that you get it because it protects it's the first vaccine that protects against cancer and it protects against cancer because the HPV HPV which is a virus the aim of hepatoma virus actually causes cancer so it's it's a pretty amazing thing with that said the recommendation is that you get three shots and people appear to be protected for as long as it's been tested but what will happen is people will continue the scientists who develop it will continue to monitor those who got it and if the immunity seems to wane then recommendations will be issue for people to be boosted but at this point it appears that those first three the primary series is what it's called is sufficient to induce immunity but again it's all yet come on down because it's all a matter of continuing to monitor people and scientists making observations it's not as exact as people would like to think you get to pick well she's picking why don't you go ahead and ask your question okay so my question is um if it was such a simple if it was just a cell then why hadn't anyone seen it before so that is the hunt $64,000 question and you what's your name poorly or lean yeah orally orally orally you get a pathogen on a cell because that is the $64,000 question why did Ralph and you can pick whatever pathogen you want that's a good one that's chicken pox so that is the $64,000 question why had all these other smarts capable scientists been looking at the very same cell cultures and they didn't see dendritic cells and that's the magic of discovery ralph was special he was special in a lot of ways probably lots of other people saw them and didn't recognize they were different so I'm gonna tell you a story that has nothing to do with immunology but it has everything to do with Ralph's discovery so have any of you ever heard of Galen so Galen was the great anatomist of of Rome and Galen this actually has to do with this so just bear with me so Galen was an anatomist who described the insides of people but he couldn't look he couldn't dissect people there were there were very very strong penalties a penalty of death for doing dissection or even looking inside people if they were trying to do some sort of procedure so what he did was he did the next best thing he dissected monkeys he dissected old world monkeys because that's what he had available to him they look pretty much like people and most of the time he was right in his anatomic drawings remained the gold standard of anatomy until the Renaissance so he had a really good run very few people's work is considered current and topical for over a thousand years but when Galen looked at the heart of an orangutan and he drew it he drew exactly what he saw which was three chambers okay the heart a human heart has four chambers two ventricles and two atria but an orangutan heart has a common ventricle so there are two atria and a common ventricle and that's what he drew but he drew that as a human heart about 200 years after galen's death not only was dissection allowed but vivisection of prisoners was allowed as the Roman Empire was decaying morals decayed along and so lots of anatomist swirling at human hearts but until the Renaissance all of the anatomist s-- drew the human heart as three chambered because Galen drawn at his three chambered and Gaylen had to be right so people were looking at a four chambered heart not even something like a cell in a microscope but something really big in macroscopic before you and they were describing three chambers because that's what they thought they should be seeing they were seeing what they thought they should be seeing not what they saw and in some measure that's what what the other other immunologists were doing they were seeing what they thought they should see and ralph saw what was before him and if you guys go out again with any one message see what you're seeing look and see what's before you and believe your eyes because there are probably all kinds of discoveries waiting to be made and that was one of Ralph's great messages was there there are thousands or millions of discoveries out there and and that's the fun of it but you have to see what's there and not what you expect to see and that's why that's why ralph was able to make the discovery that the rest of the mists the other thing that allowed him to make it was he believed himself and he stuck with it when other people told him that he was wrong I have to confess that I suspect if it had been me and everybody said oh no that's just a funny macrophage I'd say oh yeah probably just a funny macrophage and I would have moved on to the next thing but he will when you know in that video at the beginning that I showed where he said once I saw it it was simple that character trait that it was simple for him that made it different - okay I have a question oh sure okay good so just a minute yes I want to know the difference between like let's say disease germs and other pathogens was the difference between how the immune system acts on them I'm sorry like different pathogens right like diseases germs viruses how does the immune system go about fixing those problems well that is a huge topic how the immune system responds differently to different kinds of pathogens and the weather how the immune response is made is determined by the dendritic cell so the interaction of a pathogen whether it be a virus a bacteria a fungus with the dendritic cell at the very beginning of infection determines what immuno logic outcome is going to be so there are you know III would we would be here till tomorrow if I went through all the ones that we know about but in broad strokes there are some pathogens like smallpox that are terrific for the immune system they come in the immune system reacts and they make lifelong durable immunity and they clear the virus and you get better then there are some like malaria HIV and tuberculosis where the pathogens have ways of AB u of evading immunity and you get chronic infection in those cases you end up with chronic infection and it's not so easy the immune response doesn't clear the infection so those are the two sort of options and we're gonna hear more about moment in a little bit about how the dendritic cell determines those so for that you got a pathogen and what's your question if lymphocytes are very specific this is going back to immunology um then how is it that when people when a person has leukemia they get a transplant from somebody else with someone else's lymphocytes so that's a great question but it has to do with the the ability of the person who's be the transplant so when you get a bone-marrow transplant you get a bone marrow transplant because you're the cells of your immune system your white cells are malignant there and so what happens is the doctors give you a radiation or chemotherapy to ablate your own bone marrow to kill it all and they give you back marrow that's well matched so you can't just get anybody's marrow if you've got just anybody's marrow you die because your immune response would make a response to the foreign antigens on that other person so when you hear about there being a drive you know to get a marrow donor it's to find a very close match so the new bone marrow won't stimulate the immune system as being foreign so the reason that can work is because you get a very very close match and it's not seen as foreign it's seen as close to as possible with self and dendritic cells initiate that response as well and that for that you get a wait so next question my question is going back to the UM the AIDS vaccine you mentioned earlier AHA I was wondering is that does that directly protect against AIDS or does that like indirectly protect against HIV it protects against HIV infection what it pretends it protects against infection from HIV yeah and why does that only work for six months we don't know because it's not good enough but we're working on that because it's not good enough but and for that we have we have HIV in here listen HIV you get HIV there you go okay Wow okay I'm so glad for all the questions but I'm afraid we're gonna not get through so if you guys could hold them I promise I've got enough pathogens and enough bugs I mean in enough cells but let's cuz because we have pizza so I have to tell you I am somebody who comes to work every morning thinking about what I'm having for lunch and this morning is no exception so I am thrilled that you're asking so many questions in each one of you save the question I have a pathogen with your name on it and we'll get to it before the pizza okay so so this is what everybody thought was making the system go this is a macrophage okay but they were wrong and Ralph was right so when Ralph came to work with dr. Colin he started to work on macrophages because what he thought was that the macrophages which were picking up their phagocytes they pick up all sorts of material pathogens and cellular debris but they were picking it up and then they were presenting it on their surface but in fact when colleagues worked Ralph and dr. Cohen and colleagues worked on it it turned out that the macrophages rather than presenting and showing the antigens to the other cells they were degrading it they were breaking it down they were eating it up into tiny tiny little pieces so it seemed like what everybody thought was doing it couldn't be what was doing it so remember I mentioned dr. de Duve so dr. de Duve and dr. Pilate were awarded the Nobel Prize in 1974 for their discoveries concerning the structural and functional organization of the cells so dr. Pilate worked particularly on microscopy and fixation methods dr. de Duve on gradients for cell for separating the components of the cell and he described the lysosome and ralph was fortunate because they were here and this is one of the wonderful things about this institution and they were able to help him particularly doctor to do with developing these gradients now this slide was made um as dr. Creek told you my friend and colleague Michelle Nelson's why I gave the Nobel address for Ralph and many of these slides were shamelessly stolen by me from Michelle are actually given to me but this one particularly is terrific because it shows how the dendritic cells were first made and whoever asked what the but the the processes this is the slide for you so Ralph started with Mouse spleens and you're lucky to just be seeing the spleen and not where it came from and then they were put over a BSA or a bovine serum albumin gradient and then the cells were adhered to glass or plastic so the cells were put on plastic and this is how macrophages were made and so remember we I said we've started from the spleen so the cells were adhered and then the non-adherent cells were washed off and in that fraction of the cells were a mixture of primarily being t-cells and so you were left with these cells and these here I don't know how well you can see these these stretched out ones or the macrophages so then they were overnight cultured and some of the macrophages that were stuck stayed stuck but the cells that didn't stay stuck the ones that laughs that were that let go and floated up were the dendritic cells and that was actually how ralph saw them they were the cells floating over the macrophages if I'm not mistaken and so then those were taken off and there were no monoclonal antibodies so EA rosettes the Sheep red blood cells they stick to it turns out CD one but two T cells so the T cells were removed by rose adding another albumin gradient was performed and lo and behold there you had dendritic cells after two very long days of hard work you had like Maggie how many 10,000 dendritic cells not never enough dendritic cells were incredibly hard to work with because these are primary cells so you got a few thousand cells all of which were post mitotic and liked to die so the properties that were initially used to the screen distinguished them were the fact that they were non-adherent and poorly phagocytic where the macrophages were adherent and highly phagocytic these markers come later so the dendritic cells are antigen presenting cells which pick off and then process and this is really important so the immature cell picks up the antigen processes it as its processing it it becomes mature and then they present it to the lymphocytes in a way that they can be seen or what sometimes called in a cognate manner and this is a picture from Ralph and dr. Cohen's original description identification of a novel cell type and peripheral lymphoid organs of mice they were I think I thought there were three at least there were two or three two articles that appeared in the Journal of experimental medicine and they were reprinted in the November issue in the November issue so you guys might want to look at that it's they're wonderful papers and Ralph called dendritic cells dendritic cells he named them for dendron or tree and you can see their tree like processes but that wasn't his first name for them when ralph saw them he wanted to name them for his wife some some people named cells for themselves so he could have called them Steinman cells if it had been the nineteenth century that's what he would have done but that's sort of out of favor now not sort of that is that a favor but but Claudia Ralph's wife and I don't know if you mind standing up Claudia has very long arms and legs and so Ralph wanted to call them Claudia sites but I'm not I suspect that Claudia convinced him otherwise so that's how they were discovered and that's how they were named and this is another one of our beautiful glass dendritic cells from Venice and so now we're gonna seek what they do so his first work in the early 70s was simply not so simply but on discovering them once he discovered them then he figured out what they did and that's when the fun began this is a newer of okay so this movie was from Michelle and this is current this is an old but this isn't how they actually move around so the yellow cells or the dendritic cells moving in a mouse that's alive so did you all see that okay good so that's what they do they move around they stick out their processes they find antigen they pick it up and then they stick out their processes again to embrace the t-cells so this is a dendritic cell from skin so there are cells in the skin called Langerhans cells we're gonna see in a moment where dendritic cells are in the body but they they're the one of the prototypic ones and they have when you see them you see processes but in three dimension they're really almost these deep ruffles and the t-cells get engulfed and sort of held and hugged by these ruffles you have certainly seen problems like this there are real danger right stop it you stop stop it come yeah what do you think you're up to you probably infected thousands of people who are ready what do you think this is for [Music] with every breath we expose ourselves to hordes of marauding microbes these invaders are recognized by an army of specialized t-cells but whose commanding this cellular army [Music] the invaders are entering our body all the time our dendritic cell in general is on a scouting mission is hiding at the site of infection [Music] he sneaks in grabs an invader digests him and then displays the enemy's colors now he rushes off back to his troops who are waiting for battle in the immune organ barracks a nearby lymph node he shows his troops what their enemy looks like so they know who to attack after all we don't want our soldiers attacking friendly cells then the ready troops multiply like crazy now in battle they only attack the real enemies those identified by their dendritic general [Music] so Ralph Steinman discovered dendritic cells the commander's that rally the troops in the immune system wars so just to review the the cell starts out in the bone marrow goes into the blood and then it goes into the peripheral tissue so that can be anywhere in the body and we're gonna see momentarily where all those places are and it picks up antigen and remember antigen can be anything it can be a pathogen it can be pollen it can be part of your own self and the magic of dendritic cells are they then process and present the antigen on its surface and then they go into the afferent blood or the lymphatics and then they go to the secondary lymphoid tissue and they present the antigen to t-cell lymphocytes and Ralph and his team did all of the work to elucidate this entire process so when the dendritic cell and the t-cell so here's the antigen here's the dendritic cell maturing when it encounters the t-cell this is sometimes called the immunologic synapse so there are a whole bunch of receptors that become engaged that tell the t-cell so it sees the antigen in the context of the major histocompatibility locus of the individual and then the t-cell goes out and divides as you saw in that great cartoon and that's how you get cell mediated immunity the dendritic cells also interact with b-cells in not quite the same way but in a similar manner so if the beginning Ralph had a slide that I loved that had the dendritic cells as generals and the T cells and B cells as the soldiers like you saw but in the last decade he he thought it was more complicated than that and he went to this slide and this is his slide which is the elegance and scope of immunology the cells of the immune Orchestra and the dendritic cells were the conductors and in the beginning the idea was there was a dendritic cell and the first even the first 10 years of my professional life whenever I got up I spent the hour trying to convince people that the dendritic cells existed as an entity but now there are a whole field of immunology and there are more subsets of dendritic cells frankly than I can keep in my head so I'm not even going to try to teach you those today just know that they exist and they communicate and conduct a whole variety of different effector cells so the cd4 cd8 and the b-cells that we talked about as well as gamma delta T cells and K cells and NK T cells and the macrophages the basophils mast cells neutrophils and eosinophils which are morally more closely associated with the innate immune system are playing in the background as well so again a murine splenic dendritic cell from 1973 this is from the original description and we put another movie here just because they're really fun to watch so you can see again understanding that they're picking up processing and moving really fast to go find the T cell to which to present antigen and endure it excels in the beginning when Ralph described them in the spleen that seemed to be the only place they were and now they've really been found in every place including the brain for a long time it was everyplace but the brain but in the last couple of years they were described in the brain they're in virtually every organ but there they are abundant in lymphoid organs like adenoids tonsils and lymph nodes and they form a meshwork through our skin which are called longer round cells and all of our mucosal surfaces because those are the places that we encounter antigen so these are the sites that generate immunity and tolerance and this is a photo micrograph of the dendritic cells in the airway and you can see their dendritic processes and this is a beautiful picture of dendritic cells in the skin I always like it when they glow green so again to review they they come into the lymph node the dendritic cells come into the lymph node particularly into the what's called the inter follicular or t-cell area and they present antigen to the T cells they also go into the follicles and present antigen to the b-cells and this is a photograph of a dendritic cell s I'd like to say embracing a t-cell and presumably presenting antigen to it and as I said there are many not only many different kinds of dendritic cells but there are many different kinds of T cells all of which engage with dendritic cells through different receptors so here we see this is a beautiful picture from our friend and colleague Nikki Romani of the dendritic cells and from a human dermal sheet of whole skin so these are human cells so remember I told you up until now we've been talking about Mouse cells particularly those from the spleen and now we're going to move to someplace different for the afternoon so I ran out of images of the beautiful dendritic cells from Venice so now we have a dendritic cells by henri matisse who didn't actually know about dendritic cells but we were interested in one particular problem how the immune response gets started but really dendritic cells are turning out to play a role in many other facets of the immune response not only does the immune response have to be initiated but the immune system has to make a choice of what kind of immune response it makes it is estimated that there are more than a thousand different kinds of microbes or infections that can attack humans and the immune system knows how to deal with virtually all of them there's not one immune response for that thousand type of infections there are many kinds of immune responses and they have to be selected and tailored in a way that's appropriate to the infection so dendritic cells somehow knows at a sense the type of infection and tailor the immune response but in addition to infection the immune system has many other important roles that it can play one of the potential roles that many of us are studying is that the immune system can resist cancer in cancer cancers have many strategies to dampen the function of the dendritic cell so that the dendritic cell presumably is less able to generate an immune response to the cancer an allergen substances in pollen for example to which many people are allergic that allergen can affect the dendritic cell so that the vended Excel then induces what's called an allergic type reaction in transplantation when the surgeon puts on a transplant a liver a heart a kidney dendritic cells from the transplant move into the transplant recipient and teach the recipient that this foreign transplant has been put into place and that initiates the rejection reaction and then there are autoimmune diseases where dendritic cells make proteins that drive the inflammation that's seen in disease so there are many examples of where dendritic cells are exploited during the development so in the beginning ralph was occupied with showing that dendritic cells started the immune response the question he he came here to ask but it turns out the dendritic cells do far more than that so dendritic cells in their classic form begin the immune response they present antigen to t-cells they cause clone Alex and that's how you begin your immune response to whatever antigen but depending on the type of dendritic cell and depending on the type of t-cell with which it interacts dendritic cells also control tolerance or our ability to tolerate the the cells in our own body the reason that we don't make an immune response to us the the young person who asked the question about a bone marrow transplant the reason one can accept a transplant is also due to dendritic cells and that work has been done in the last decade so as I said we began with dendritic cells from mice and these are dendritic cells from people so in the beginning the cells had to be isolated and that took days and a lot of mice and a lot of work and it really limited the amount of discovery that could be done in the mid 80s recombinant cytokines were developed so so synthetic biologics that affect how cells work and grow and so it became possible then to take precursor cells of cd34 progenitors from a human being and treat them with cytokines and make dendritic cells teach them to become dendritic cells so you can grow dendritic cells and culture and make more of them which is part of the reason that other people began to work on them because before that it was just so hard and so frustrating that not that many people wanted to spend their time doing it so Theobald Smith was the first director of the the the Scientific Advisory Board of the Rockefeller Institute which is what this institution was called at its founding and he figured out about diseases being caused by vectors and this is one of Ralph's quotes from him and I love it um the objectives of research is a mere accumulation of data or the display and parading of acquired knowledge in a world otherwise in motion is outmoded discoveries and inventions must be made to yield some contribution towards that rather vague goal the welfare of mankind and he said this in 1934 and think it sounds pretty good today - so with that sad even though understanding dendritic cells was tremendously important Ralph was far from satisfied with that and he extended his work to to work on how to manipulate them to make the world better so the critical experiment that demonstrated that dendritic cells actually are nature's adjuvant and present antigen was done by our friend and colleague kayo Inaba in the early 90s and so in mice she took out dendritic cells from from the spleen from the immune organs or she made them in vitro the methodology I described she added a protein outside the mouse and then she reinf used them she gave them back to the mouse and the mouse was able to fight off whatever the error or make a response to actually make a response to this antigen and that experiment laid the groundwork for the use of dendritic cells in immune therapy which you're going to hear about this afternoon so here we have the same idea Kyle's experiment in a person so you take out blood cells you make take dendritic cell precursors you expand them using cytokines you add an antigen like a vaccine and then you give them back and lo and behold the person makes a really robust immune response so with that we're going to break for lunch it's only 12:03 and time for pizza um I don't know if we should have the quest the rest of the questions now or maybe hold them for the we'll hold all the questions for the end hold them hold the questions for the end I think pizzas we don't have to be today at cold and thank you very much [Applause] well welcome back I hope everybody enjoyed lunch and this afternoon we're going to move from Ralph's basic discovery of dendritic cells into the medical applications and it's my pleasure to introduce my friend and colleague marina kaske who's worked with me and with Ralph for the last five years on bringing dendritic cell biology into the clinic and she's going to tell you about our work with Ralph in that regard I see you guys all waiting for your questions and we're going to have all the questions at the end and I will stay as long as you want as long as our questions will stay and there are lots of bugs left so let's let marina talk a little and then we'll have the questions but I have to tell you you guys have made our day by asking questions so remember what they are we want to hear them thank you so much for coming back after lunch so like Sara mentioned so first I want to say that it was like Sara said my relationship to the lab is has been a lot shorter than her relationship I've only been in the lab for five years so for me is really a great honor to be able to be here today and then share with you what I've learned and then the work that we've been doing together so we learned a lot about dinner the discovery of dendritic cells and what they do but was always very important to Ralph to bridge the knowledge the scientific knowledge in animal experimental models to make a difference in medicine and like we heard from one of his Clips this morning our immune system interacts with with many types of diseases so we learned that our immune system can fight and resist infections and it can do the same to cancer but it can also be involved in rejection to transplants and in the pathogenesis of Ottoman diseases and allergies and in the middle of all of this are the dendritic cells since they are the cells are orchestrating the the immune responses so we believe in the lab that we can by studying the genetic cells we can understand disease development but not only understand how disease evolved but also use dendritic cells design new treatments and new vaccines in our focus now is on developing vaccines so let's see what Ralph had to say about vaccines so let's just think a little about a vaccine what a vaccine is is typically an infectious agent like the polio virus and that virus is inactivated or it's attenuated so that it is less virulent so that it can no longer cause polio and you then administer that vaccine typically by an injection into under the skin or into a muscle and the immune system takes that information and develops resistance to the vaccine in this case the polio example that I've brought up so that when you would be exposed to the real polio virus you have the capacity to reject it and prevent the body from being infected but now along comes a situation like the AIDS virus what we found is that when the AIDS virus interacts with the dendritic cell the dendritic cell provides it a home that allows the virus to be transported to the lymphocytes where the virus then replicates so the evidence says that the dendritic cell is exploited by the AIDS virus to be carried inside the body and to replicate to large numbers but there's another side to the coin a second side which is that dendritic cells can be used to design Prevention's and therapies for disease we have been studying how the AIDS virus interacts with dendritic cells how the AIDS virus uses or exploits the dendritic cells for its own purposes about the body and to replicate and we're also studying the AIDS virus as the premier example of where we need to use immune principles to design that the design vaccines that's what's he said so what is a vaccine so vaccines are substances that I use to stimulate a production of antibodies not only antibodies but also then print a message into t-cells and so that it provides immunity against one or several diseases it is usually prepared from the causative agents of disease from the bug that it's causing that infection or a synthetic substitute and the orange the origin of the name comes from vodka from cow because of the early use of cow pox against the smallpox so vaccines are among medicines greatest successes it is because of vaccines that we no longer have smallpox for example but they are still urgently needed to prevent and treat some medical problems such as AIDS cancer and many other infections so how vaccines came to be so like Sarah said it was known since ancient Greece that once someone had was sick with an with an infection though I don't think they knew there was an infection but they recovered from that that person that recovered could then take care of the ill because they could no longer have the infection second time so this knowledge aid was the basis for a concept of the concept of this technique there is used in China and India in the 11th century with the concept called variolation so the concept behind this technique was to give a very mild form of smallpox in order to provide lifelong unity since we knew that once someone survives an infection that person can no longer have an infection so why not give a weak form of that disease so that the immune system can learn in the never get it again so what they did without necessarily knowing what caused the smallpox they collected scabs from from so do you guys know what smallpox was like so it causes blisters that then created these pock marks and that's kept over and left these scars for life so they used to collect the scabs and dry the material and then somehow they realized that it was the way that I was transmitted was not necessarily from the skin but it was from the inhaled droplet so there was virus in the mucosal the oral mucosa and then true droplets the virus that infected that person so with the material that they collected from people that had recovered from the scabs they then would this is a painting showing a person blowing into someone else's nose that material because somehow they realized that that would then create immunity in the against email pox and this was used for for a while but there are problems with this the problem was that for the most part the disease was was a mild disease and people would recover but there are some okay in some cases it wasn't quite like that and then some people died also because they were they they got a smallpox those people that were then very alized they could then transmit the disease to another person so wasn't an ideal vaccination so years later Jenner it came to his attention that milkmaids the even though if you went to a village you'd see a lot of young ladies with these terrible marks of smallpox but he noticed that milkmaids didn't have they had perfect skins and he also noticed that even though their skin was perfect didn't have the pawl marks the pock marks they had some of them had blisters on their hands and that it was known that caddo could have a disease called cow pox and then probably the milkmaids were being factored with cow pox where while they were milking the cows so he then proposed that perhaps cowpox the effectual cowpox was cross protecting people against smallpox and then he did of two key experiments in 1796 where he collected fluid from the blisters of a milkmaid and then he then scraped that material onto the skin of an eight-year-old boy and then that boy then developed little lesions in the steam and then when he was then challenged some time later with actual smallpox he never got sick so he was able to immunize to take Michiru infectious material from the milkmaid and then vaccinate the boy with that material and then prevent the boy from getting smallpox and this is where vaccines come from and then it was a long story in the for smallpox oh so long story ending in the late seventies when it was eradicated from the world through vaccination so but he did all of that with knowledge that we have a new system and then we our immune systems our bodies learn how to fight infection and then can no longer have that infection however he that that time there was no knowledge of what the organisms were so a century later comes with us there where he he then initiates what we like to say rational vaccine design so during his time one could already isolate organism and grow them in culture and then Pasteur was working with cholera and chicken so he would grow collar the bacteria and then infect chicken and then he would in fact such a high dose of color that the chickens would die so he went on a holiday and then he left his cell cultures to the care for his assistance but the assistant also went on a holiday and then when he came back when they both came back some weeks later and they used that culture that those cholera germs to infect the chicken they got sick but they didn't die as it was expected so the assistant said you know I think we better off throwing away this new sculptures because they are no good pass there on the other hand he realized that maybe something very interesting had happened and there comes a quote where chance favors the prepared mind so he realized that there's something special in what he did was he then tried to affect those people with virulent with active cholera and they never got sick again so what happened was that in that those old cultures that the bacteria had become a 10-way and they was weakened and then it caused very mild disease and then the chicken could never be infected again so that is the beginning of live attenuated vaccines and then he went on to make that other vaccines like against rabies and then other researches created all these other vaccines over the years so but how the vaccines work so recapping from this morning we learned that the immune system the immune responses are specific they are directed against the specific pathogen they are diverse that's why we can we can respond to so many different pathogens and microbes that we are constantly exposed to and then once you have you built a very strong immune response your system your body forever remembers there is memory and then you can forever fight that infection so how does it work so the vaccine borrows from these properties of immune responses to teach our immune systems to resist infractions using the same mechanisms of a natural immune infection naturally responds so the resistance likening an enemy response should be specific for the infection and then it should typically be durable and the reason would say typically is because you guys already came up with is that sometimes for vaccines we need to have reboost vaccination because unlike natural infection sometimes the vaccine does not induce long lasting immunity so every so often we need to boost those immune responses then wane over time there are many different types of vaccines so the first vaccine was a live attenuated vaccine but vaccines can also be inactivated meaning the the the the bacteria or the virus is completely killed but still has the antigen still has the structures that teach the new system how to fight it they can be subunit vaccines so protein or polysaccharide vaccines so these are vaccines that have only a particular structure of that bug that immune system can then recognize and then build an immune response against and there are more recent experimental type of vaccines like DNA or viral vector vaccines so why do you we say that vaccines are great successes so if you look here this is this sums up the the the ideas so here are many of the vaccines that we've received and this column shows the number of cases that were around in the United States before vaccination was routine for each of these infections and then many years later after vaccine was routine you see that prison for diphtheria it no longer exists the case of measles and mumps have dropped polio is it's gone in the United States and then smallpox is eradicated from the world so this to me really captures why vaccines are so important in why vaccines have been able to help us almost get rid of a lot of these severe infections however we still need vaccines for certain important severe and chronic infections like for example tuberculosis where a third of the world's population is infected with TB and even though there is a vaccine it's not such a great vaccine and it can't really protect against the most common type of tuberculosis which is pulmonary tuberculosis in the case of malaria again is a very present infection that can that kills a lot of people and we still don't have a good vaccine there are experimental vaccines being tested but they're still not quite good enough and then in the case of HIV over 30 million people are infected millions of people get infected every here and then there is some hope that a vaccine can be made but the best that we have so far is a vaccine that can protect only a third of the people in like Sarah mentioned this morning the protection is very short-lived so it's again not ideal beyond the scientific challenges we also have to keep in mind that it's not only it it's not only having the experiment making the vaccine you have to implement you have to make people believe that vaccines are safe and then people accept to receive the vaccine so for example with polio we have a vaccine it's a very effective vaccine there is an eradication campaign against polio since the late 80s and still we have polio cases in a few countries in the world because primarily because there are cultural issues preventing people from coming forward and being vaccinated and in political issues so we have to keep in mind signs but also society and then how we can implement science to eradicate disease so how does a vaccine teach the immune system to resist infections so capturing from from what we learned in the morning so when a person is exposed to an infection or a vaccine which is a mimic of a faction the dendritic cells realizes danger entered the body and then picks it up and then processes and presents on its surface and then goes to the lymphoid organs to interact with the lymphocytes and then it finds the lymphocyte very specific against that infection and then teaches the lymphocyte how to fight it in the leaf asides then go and then can clear the infection all the lymphocytes learn how they would fight the infection if it's through a vaccine so that in the future if you've ever exposed the lymphocytes you know to go and kill and you never get sick so vaccines are a safe way to mimic infection so again learning from recapping from the morning there are different ways to resist infection there are different parts of the immune response so the first part of the immune responses they maintain in response it's what happens right when you a foreign organism enters your body so this response is quick it's nonspecific so so the all these cells are just releasing these different cytokines and it's gen its general it's not specific for any particular organism that just happens to everything and but it leads to no memory so it but it can kill some microbes early on then few weeks later so they made response that's the stage it's when the dendritic cell picks up the microbe and then goes to teach the lymphocytes how to fight infection and a few weeks later the B cells and the T cells are ready to fight the infection they already learn their lesson so come so then comes along adaptive immunity which is slower than the innate immunity it's specific and then it should last for life so and the dendritic cells are in the middle of this they are really linking this early innate immunity to the adaptive immunity they capture and sense microbes and then they initiate and control the type of human responses that enter so when a microbe or a micro dynamic in the case of vaccine we encounter microbe that leads to an eighth response that an matures the dendritic cells the dendritic cells and travel to the lymphoid organs where they meet the circulating T and B cells the finding specific ones they expand and then they travel back to the area of infection and then try to clear the infection so now just a few concepts that we've been talking about but we haven't yet defined so what is an antigen an antigen is any foreign or abnormal substance like a bacterial virus or tumor cell that stimulates the body to produce antibodies so this is a picture for bacteria and then here's the antigen so we can think of the antigen as the building blocks of the different viruses and bacteria and these patterns are what our bodies recognized and then realized that had that they have to fight and clear so antigens are what vaccines are made of but some vaccines also need to be given together with an adjuvant and what an adjuvant is it's an immune booster so these are substances that I use in combination with a specific antigen to produce a more robust a stronger immune response so that to the antigen alone and then these advents are included in a lot of the vaccines that we take that we receive so now knowing all about how the dendritic cells key in the in the setting the stage for immunity and how most of the vaccines are made from from attenuated microbes we ask the question can we then make new and safe vaccines they are composed by only by the antigens by these defined components that actually directly on the Hritik cells to bring about me responses so thinking about that researchers have come up with two different approaches to use in dendritic cells for vaccines in one approach which Sara alluded to this morning you use dendritic cells for the person so you generate dendritic cells ex vivo so what that means is you take a simple blood you isolate the trick cells they are expanded in the cinah culture and then they are loaded with antigens and then you refuse so in that way you have a personalized cancer vaccine for example but as you can imagine is very labor intense and then it's only done for that one person so probably be very difficult to to bring it to a scale of an HIV vaccine for example another way of to think about a dendritic cell is to figure out a way where you can deliver these antigens or these tumor cells directly to dendritic cell in the body so you didn't drag to the antigens and the engines would find their way to the neurotic cells and invite by in that way they would then induce in response so these would be more generalizable vaccines against cancer infection and perhaps other diseases so this is a low station for the morning talking about the first approach so the person donates blood the dendritic cell precursors are isolated then with a mix of cytokines they expanded the antigen is then added to the culture the dendritic cell matures present processes and presents and then these cells are very few x'd and then they'll know now know how to teach the body the person's lymphocytes how to fend to fight cancer for example and these are some of the labs that are working on this strategy and in 2010 the first vaccine using this concept of isolating and antigen presenting cells and then adding the antigen in vitro and then refuse it was approved so the vaccine is called prevention and it was produced by this company called danger on and then it's it's a similar principle where the patient undergoes looking for reasons which means their lifestyles are taking out the cells are then mixed with antigens against prostate cancer and then an activating substance called gm-csf and then three or four days later the person is being fused with those cells and then they were able to show and the reason that they were fda-approved was that this type of vaccination prolonged life of patients with advanced prostate cancer so there's the beginning of the time why we can think that immunotherapy and then perhaps therapies based on the genetic cells can be effective against cancer but there's a long way to go to make this better so but we were not working on this in the lab we were working and we are thinking of this in a different way so we are we were using features of dendritic cells to design to design vaccines and then we are focusing on two concepts the antigen we thought that the antigen should be the fine component of a bacterial virus and they should be directly delivered for dendritic cells and one way to do so is to target them to the sub take receptors and I'll explain to you with what those are in a little while these antigens then have to be given together with adjuvants which are those immune boosters that I told you about in in a way the one type of adjuvant are molecules that that link that signal through these pattern recognition receptors which are sort of antennas that we have that there are protect foreign dangerous signals when we exposed to them so together this is the vaccine concept that we are working on so that's well but Ralph will probably explain it better so let's listen to him we're learning to direct the vaccine proteins to the dendritic cells in the patient so we don't have to take out the dendritic cells or make them outside of the body it's much simpler to make a vaccine that knows to go to the dendritic cell and knows to be delivered with other stimuli at the dendritic cell needs teach the immune system to protect us this approach we think is not only simpler but more amenable to translation into global infections mater and simpler okay so what are those optic receptors so we learned that there are many different types of dendritic cells and then each type expresses receptors on their surfaces there is lightly different from each other and there are many of them and then what these receptors do is they can uptake certain ligands or they can act take antigens and then so that's how things go from the outside to the inside of the middle Excel and then they can be processed and presented and in our lab we are focusing on this optic receptor called Dec 205 which was discovered both by Ralph and by Michel nuisance by one of his very close collaborators and why do you think that this uptake and aesthetic receptors are so interesting because they interact with microbe and self ligands so they can enhance antigen uptake and presentation it's a lot more efficient to bring antigens to dendritic cell if you bring them through these object receptors but they can also allow the drilling cells to mediate infection so I like I sign that video earlier on HIV can hijack a dendritic cell can enter through one of these uptake receptors called DC sign and then it can be incorporated in huge it excels and then be carriage to the other cells of the immune system so if we have anti receptor monoclonal antibodies so antibodies that bind to these receptors they could then be used to deliver vaccine vaccine antigens for improve vaccination and so that we could also study the interdict cells so this is the the receptor that we are focusing on is Dec 2 a 5 it has ten electing domains and it's expressed themselves their dendritic cells are very abundant in the t-cell areas of the lymph nodes which make this very special because the those cells are in very close contact with blue T cells so that when they are presenting intogen it makes it easier for them to find the specific T cell for that particular antigen and this is a picture by Maggie who's here in Angela showing the so all of this red R vector v expressing the nude excels in the T cell area of the lymph node and you see that there's some of it too in the B cell areas so they're real in close contact with the T cells are circulating through the lymph node so that they can select which ones are needed to fight that particular challenge so so this is a diagram of what our our vaccine is so we have an antibody and anti by and you learn what an antibody looks like and from the morning so this antibody it's specific it binds to one of these optic receptors in this case vector v and we linked antigens from HIV or from cancer or from other infections from autoimmunity diseases like multiple sclerosis we linked to to the back of the antibody if you will so that when they update the antibody binds to the receptor it's taken up and it carries with it the antigen so then the Virgin Excel process the antigen and then can present to the T cells but in order for that to take place the antibody has to be given together with an Agilent so that didn't drink so the edge of and what it's doing is causing inflammatory response so it's telling the dendritic cell hey this is not good you have to fight it so you have to present the antigen where's the alarm signal so that the little exhale nose that it needs to teach the lymphocytes how to fight that particular infection so the arguments are we using are like I said our ligands for these toll-like receptors and what they are they are researchers that can detect microbial patterns that are not expressed in healings and they alert the body of an infection and they were also awarded with the discovery of these receptors was the second half of this year's Nobel Prize and I guess the way you put it together is once weird we we are invaded by it by a microbe the body detects the presence of the microbe by signaling by recognizing these patterns that only bacteria only viruses have this de said these receptors alert the cell that cell being an intra dick cell then jet excelled and picks that microbe up it chops it up and then presents to the rest of the cells so this is how the innate response is linked to the adaptive response there are many different types of TLR receptors they recognize different different parts of bacteria for example tlr4 recognizes LPS which is on the wall of gram-negative bacteria tlr3 which is what we are focusing on recognizes double-stranded RNA that it's it's a pattern in viruses so you could eat we are texting different were different of these ligands but so far we've had the most success with ligands for this type of tailor so just to illustrate what I've been trying to explain so what is our Davidic cell targeting strategy so as I said he is a dendritic cell they have on their surface dec 12 5 optic receptors so then we give this vaccine that consists of an monoclonal antibody carrying in this case HIV antigen we give this in the skin of the person that finds the dendritic cells there are in the skin the dendritic cell then picks up that antibody with its antigen processes the antigen and presents on its surface and then a try to the leaf node where it's gonna meet the recirculating cheese cells and then we'll meet those specific B cells and I know the induce immune response so then this lymphocytes will travel back to the periphery and then will always will be there hopefully for a long time to fight an infection later on if the person is ever exposed to that infection and then we think so we are first focusing on HIV but we think that we could use this those exit strategy to many other diseases not only affections but also cancer and autoimmune diseases so our first focus is on HIV Nia this is a picture of HIV and then it's different components in one of the reasons that we focus on HIV is not only to prove that we can make it a dendritic cell base vaccine but it's also because HIV even though we have effective treatments continues to be a major problem and it is a major problem especially in underdeveloped parts of the world like in Africa so like I said even though there is treatment we can't keep up with it so for every hundred people they are put on treatment 250 are newly infected so we always falling short so we really need to focus on prevention there are many different ways to prevent HIV and none of them are perfect you all know about barrier methods condoms how effective they can be if they are well used circumcision it has been proven to protect against HIV and then these other modalities are more recent than they're still being under a study where you could give someone HIV nights either before or after they've been exposed to HIV but again this is still under study it shows promise but it's still under study and in the same way we can say that if we treat HIV infected people because we bring the load of virus to be so low that can also decrease the likelihood that that person would then transmit the infection to another person but is can see none of these are perfect and so and so really what we need to focus on is on a vaccine on a highly effective vaccine but that has been proven to be very hard and then some of the reasons that it's so hard is because HIV is a very tricky disease is a very tricky infection first no one is ever cured from from natural infection so we can't really learn from from from the immune system what how to make a vaccine the virus in one of the reasons is because the virus is very variable so you can measure your immune system even if it learns to fight virus a the virus is always changing so you never know how to fight the new strains that that come up every day the the virus also knows how to hide from the immune system so it it integrates into the host genome and it doesn't divide it just stays latent so the immune system doesn't see it and then to make it things worse it only infects humans so then it's very very hard to study it we have models of MA in mice and modeling in non-human primates but they're not they're not perfect so all of this together make make an HIV vaccine extremely difficult so in if we believe that what a vaccine needs to do is needs to induce antibodies hopefully they could induce neutralizing antibodies that then would block viral entry and they should induce cd4 and cd8 t-cells where cd8 t-cells would then be able to if the antibodies failed to block entry and the cell got it got infected the cd8 cells could then kill these infected cells so we want all of this from a vaccine and it's been proven to be very hard those are the t-cells help so many many candidate vaccines have been tested and the best results to date came from a large study conducted in Thailand where it was a very complicated vaccine regimen and then it provided only 30 percent protection that waned over time and this is just to illustrate the trial workers in Thailand and really what I wanted to remember is that it took 16 over 16 thousand volunteers to to test this vaccine to show that this vaccine did provide some protection so it was really a major endeavor on on the size of the scientists and the volunteers so so what are we doing about it then so we have our intellectual 5 antibody and then we linked to it the HIV gap between the 4 antigen and that we then give this together with immune boosters so that the neurotic cells know that they have to do something about it and this has been done in collaboration with a biotech company called celldex so this is just to illustrate that then drilling cells are usually in an immature state where they can capture antigens and then when they see the edge of and then they mature and then they learn that they have to teach the lymphocytes how to fight that infection how to build an immune response so we tested this in mice and then we can tell the mice that we induce some immune responses we induced responses are of high magnitude windows responses that recognize different pieces of p24 it's of high quality the responding cells make many different cytokines and then in a very restricted experimental model in the mice we can show that the mice era immunized could be protected from a virus that expressed HIV but again it's all very artificial so we knew that we needed to then move from the success of experiments in mice to people and then this is what I feel that the study of humans is a very important area for discovery for research often we use the word translation the contrast weather might think we use the word translation to indicate that we know something from a simpler system like an experimental animal such as a mouse and we simply have to translate it apply it to the human condition but I feel otherwise I feel we have to study the human condition to discover the relevant scientific principles so cancer is an example cancer is a very difficult disease to model in an experimental animal so we need to do research in humans with cancer to really learn how the immune system deals with something like a cancer cell can the immune system teach the body that a cancer cell should be treated as if it were an infection and the immune system should attack it and the potential of the immune system is that it is able to see many changes and many changes are occurring in the cancer cell at once so if the immune if the cancer cell tries to escape the immune system is seeing so many of the alterations that it's very hard for the cancer cell to escape but still the immune attack as it is an infection it's highly directed it's highly specific it's usually non-toxic it really targets in on the cancer cell or the infection and I think this provides the potential for a whole new type of therapy and cancer but we need research and patients to discover the rules to discover the principles so but how do we do studies and humans it's not very easy these studies have are highly regulated by the FDA and then you have to go through a long process through various phases until what drug or a vaccine is finally approved for use so you know and you might have heard about these phases of human studies so first have to go to a phase 1 study where it usually studies of tents about 30 40 people and then the focus of this study is you give you administer a vaccine or you administer a drug to two volunteers to healthy volunteers usually and then you're looking for safety you first and foremost you want to make sure that your new discovery is not harmful it has to be safe once you pass that and but you also like to see a hint that it can be useful so then you sorry so then you go on to a phase 2 study and then in the face to study then you're involving about 200 people or so and in the case of vaccine what do you want to show is that the vac you show that it's safe and now you want to show that you yes you can induce immune responses so you can measure that the person after receiving that vaccine makes antibody against that particular infection or has t-cells that can fight that infection favourite the person is exposed to it once you do that then to really show that a vaccine has efficacy that it can really prevent an infection you have to go on to a phase 3 study that involves thousands of people and then you saw in the case of the Thai trial for HIV that it had to involve 16,000 people and you can only imagine how costly theirs is and then how long it takes so here in the hospital we carry on early face trial so we do like well said we do studies in humans we try to prove our scientific concepts into humans and then we conduct this early phase smaller trials mostly in healthy volunteers and one of the studies that we did in our group we I thought I told you that one of the the adjuvant that we're focusing on is ligand for tlr3 since the double-stranded RNA called poly IC so we needed to we knew that it was safe from from prior studies but we needed to understand how it activated the immune system because that would help us design up the trial for a vaccine so we gave poly I see to people and then we studied how people responded and then we saw that the first the first and the second day after the season policy everyone developed an inflammatory response so everyone had their arms standard they had an area of readiness and along with that when we checked in the blood we saw that they were up regulating different genes genes that were involved in fighting infections and then we compared these genes to to a very effective vaccine to the yellow fever vaccine and then we saw that both the yellow fever vaccine and the adjuvant were inducing very similar genes so then that made us believe that this is a good event of an appropriate age vent to alert dendritic cells of a viral infection or to tea to help the trick cell uptake that viral vaccine and then teach the body how to fight a virus but really our focus is to bring the concept of Bend Hritik cells of targeting antigen studinger excels to the clinic so I told you about that receptor and that was discovered in 1995 and then after a series of studies in in animals and safety studies in both mice and non-human primates were able to 15 years later start our phase one study of this compound so it's live is again just to illustrate how long things take and then how you have to stay focused and believe in what you're doing so we started our study in June of last year and then it took us about a year or so to screen over 500 people so 500 people actually stepped forward and incall those were willing to volunteer for our study and then out of this 500 we enrolled 45 people in the three arms of the study and in this study is now ongoing so took a lot of work on our side to find these people but also takes a lot of commitment from them to participate in the in the study so not only they they are going to receive three doses of the vaccine over a period of three months but they're going to be followed for another year there and then all these red lines are all the times that they have to come back to the clinic because we need to both make sure that they don't have too many side effects of the vaccine but we also want to collect blood so that we can study the immune responses that they are making so all you know it takes a partnership between the scientists and then the volunteers because without the volunteers we can do the experiment in our study is currently ongoing and then we are blinded as to what the volunteers really received but we know that they are making antibodies against the vaccine so I think this is a quote from Ralph from the series of quotes that I received from him and then he here defines why he thinks patient base base research is important so he says being explicit about patient base research it is exasperated in the number of significant obstacles that must be overcome is essential for better understanding of disease development and treatment it's equally profound two other spheres of scientific research and it's exciting and we agree with them so now I think we I've made the point that vaccines can be very successful past era is the first one to manipulate microbes to make vaccines but now we want to do but these vaccines were always based on the microbe they're always based on microbiology now we want to apply all that we've learned in immunology and the dendritic cells to make vaccines they use the define antigens and the adjuvant so that we can hopefully be able to prevent infections and other diseases so in summary for today I hope that you go home knowing this new set that the cell that might be new to most of you called interdict cells they and they have three major features they service sentinels as they they are present in peripheral tissues so they are guarding our bodies they can sense when there is an invader and then they can respond to that conducting the rest of the immune system to respond fight and resist whatever the challenge might be our hope is first to help develop an AIDS vaccine this has been a long-standing and really challenging problem one part of the problem is that we don't know how to elicit T cell immunity so a second hope I have is that by learning to do this in the setting of an AIDS vaccine will it be able to extend our research to other vaccine needs larrya tuberculosis leishmaniasis are all infectious diseases that are in our research strategy and above all we also want to bring vaccines to the field of cancer cancer immunology is ripe with potential to help patients resist their tumors we need to design approaches in humans to test the capacity of the immune system to bring this about so that's thumbs it up so we are starting with HIV but we are very ambitious we want to be able to have an effect on many other diseases [Applause] so sorry for the little bit of confusion with the two of us but we were trying to coordinate nature so I'm going to talk at the end about a little bit more about cancer immunotherapy and about Ralph in particular they think now would be a good time to take the rest of the questions so do the questions now and then we'll do the end at the end so for all of those of you who have questions I hope you remembered them and we will do our best to answer them and we still have plush toys and we still have plush dolls okay hi I have a question about dendritic cells okay in the rection on one of your slides that the immature dendritic cells help like other like lymphocytes no which basically which antigens are self antigens right it helps with tolerance right so immature dendritic cells right established tolerance or silence could you describe a little bit about how that works well dendritic cells so there are many different time types of dendritic cells and dendritic cells control both arms both types of immune response so they both establish immunity as you would have to a virus or to a vaccine but they also teach the body teach the lymphocytes in the body what antigens not to respond to so probably the most in quantity the the most quantitative antigens to which were exposed every day are our own dying cells so it's immature dendritic cells that deliver a signal in concert with the MHC the major histocompatibility complex to go to the T lymphocytes to a special subset of T lymphocytes that are called regulatory cells that tone down the immune system or induce tolerance so they do it through what are called T regs so sorry just like do they do that while the t-cells and b-cells are maturing or like how does that work yeah so the way I think of it is if you so when the dendritic cell encounters something that it's supposed to to see and then make the immune system fight it it's it's where it sees that in the context of an inflammatory response it so.when so for example we are being exposed to food all the time and then anything can be an antigen but our bodies receive food and in a way that is not induce any an inflammatory response so it's not telling the dendritic cell hey I'm a bad thing you have to fight me so it's in that context that when the deranged house finds foreign substances without a context of a danger signal it doesn't mature it takes it up and it presents and then it teaches the cells of the immune system look this is okay you don't need to fight it on this side how does our immune system recognize whether a pathogen is good or bad I think that dr. chaski just pretty much answered that question it has to do but there isn't good or bad it's whether it's dangerous or not whether an inflammatory response need to be mounted needs to be mounted and so that has in large measure to do with what's foreign and what has these what are called pattern recognition receptors so there are these special signals that come from viruses say double-stranded RNA viruses have double-stranded RNA mammals don't we only have it in a single-stranded fashion so double-stranded RNA tells the bot the mammalian body a human body that it's dangerous that it's a pathogen bacteria have endo endotoxin they have lip special molecules that signal in that same way in a related way through these pattern recognition receptors are the TLR like receptors in one of the purposes we're forgetting we're forgetting you to coming down come come come I'm sorry okay in one of the previous slides it said that dendritic cells were in the tonsils mm-hmm so if you get your tonsils removed does that mean that your immune system is weakened because of your loss of dendritic cells well that's a very good question not only your dendritic cells in tonsils but the tonsils are full of lymphoid tissue they are almost a completely composed of lymphoid tissue and people have wondered about that there and and the dogma or what people understand to be correct has gone back and forth clearly people live long and healthy lives without their tonsils like me when I was a little girl I in 1963 my tonsils were removed just because I had them okay if they had they would see articles in the newspaper about whole families being brought in to have their tonsils taken out just because they had them and because the doctors could we've come to realize that it's probably never a good idea to remove anything in that fashion but and there have been studies that have suggested that there are some complications to having tonsils removed they don't believe any of them have ever been born out and I guess about 15 or 20 years ago a series of very rigorous criteria by a group in Pittsburgh doctors blue stone and stool were developed which have been generally accepted as to how many infections one has to have to make it worth removing the tonsil so in some ways I guess the jury is out but but you're right and that you lose not just and Hritik cells but a lot of immune tissue but it seems to be that benefit for people who have chronic infections and are sick all the time seems to be worth that risk come get your white self or your pathogen I was wondering if it's possible can you speak up a little word I was wondering if it was possible for the T cells to target other T cells if they look like antigens that were specific to that place yes it is possible for the t s-- for the body to make an immune response to itself and in in some autoimmune disease T cells can be the subject of that immune response how exactly that gets turned on I think remains a mystery at this point you can come down next I have a question about vaccines great um when vaccines happen and then we develop like memory cells how do the memory cells work do they stay active like looking for the pathogen or there they dormant until this until the pathogen comes into her body so that's a very good question the memory cells don't stay active the memory cells have a very actually relatively short life and they circulate and then they a small number of them become quiescent and they they they become resting cells and they they they sit there for a very long time and resting cells can have a very long life almost the whole lifetime of a mouse and probably the whole life close to the whole lifetime of a person and only when the pathogen or the antigen comes back and then you have to mount what's called a memory response or a secondary immune response which is easier to do it happens faster and it requires less and in fact dendritic cells can be involved in it but they're not required other cells could present antigen then the memory cells come out of the bone marrow and very quickly proliferate and again you've got your response and that's the fundamental basis of memory but the cells have to rest quietly and quiescent ly for a long time and can up for a long time in the marrow thank you comeget awake so why are humans able to obtain the virus of HIV but animals aren't because HIV so the way that HIV enters the way the HIV infects is by hijacking white cells and in so to enter the white cell the HIV virus needs to bind to receptors in fact the cd4 cell that defines that type of lymphocyte so needs to bind to cd4 it needs to bind to another receptor that on human cells beyond that the machinery inside the cell so that the virus can replicate and then can then kill that so as an effect other cells only humans have the proper enzymes right so some so for example in the mouse they cannot the city for molecule on the mouse is not the right type further further for HIV so I can't really enter the cell beyond that in other animals if it enters the cell it cannot replicate so then it doesn't become a productive infection but there are other there's viruses that are similar to HIV for example there is a an FIV for cat so they can infect catch so it's a feline immunodeficiency virus there's a SIV seen in immunodeficiency virus that infects monkeys so all of these are related and then all of these viruses are used to teach us how HIV functions or yeah causes disease there's a virus in there for my question has to do the immune system and chickenpox I was wondering if it's easier for a child to fight off chickenpox and an adult to shingles and if you have chickenpox can you still get jingles okay so let me answer the question backwards you can only get shingles if you've had chickenpox so shingles and chickenpox are caused by the same virus a virus called varicella and what happens with chickenpox as you get an initial infection and you get a viral syndrome I guess probably all of you at the chickenpox vaccine but I can speak with great authority having had natural chickenpox it's miserable you get a fever you feel sick and you get these itchy pox lesions all over your body including inside your mouth and yeah it's really unpleasant but your immune system fights it off and I think we're missing that but there were some chicken pox in there your immune system fights it off and you recover and get better but the virus has a special capacity to live in nerve roots or in ganglia and the immune system keeps it in check so even though it's there nothing happens but then as you get older if you become relatively immunosuppressed for some reason you have an inter current infection you get pregnant or you just have the natural immunosuppression of aging which happens that virus can pop up come travels down the nerve that's why shingles follows a nerve distribution because it's being spread along a nerve so you can only get shingles as you've previously a chickenpox and the same vaccine which is given to children to prevent chickenpox is now being given to older people to prevent them even though they've already had the virus from to keep their immune immunity to the virus up so as their natural immunity wanes with age the vaccine will boost it and prevent them from getting shingles thank you come and let's see if we've have a chicken puck there for you you know if there any left yes hi my questions about vaccines and for childhood diseases how are you able to get a vaccine that's combined for like diphtheria tetanus and pertussis how are you able to get the vaccine all at once are you able to get the vaccine all at once oh that's a terrific question and when we were sitting down to put these lectures together amoreena mentioned mentioned it briefly but there are all sorts of challenges in making vaccines that are not strictly speaking scientific and one whole group of them are what's called formulation and that is how do you make the stuff how do you get it into a vial how do you keep it sterile and how do you keep it cold so one of the great breakthroughs in the Pulte in eradicating polio and i think we have enough time for me to tell this story so polio vaccine has to be kept cold there's something called the cold chain if you think about it when if you need a vaccine to go from here to New Jersey it's pretty easy you put it in a box with some dry ice and you go from one freezer to another but if you're in Cameroon and you're in I owned a and you're going out to the bush there may not be a reliable source of refrigeration where you're going transportation may be slow and you may hit a tree across a road and if the vaccine gets warm it's no longer useful so I don't know how many of you have little Hot Wheels cars you painted with hot water and they changed color or those dolls and you could paint on their faces and they got like lipstick on them with hot water so that invention has actually saved millions of lives with the polio vaccine so there are now labels on the polio vaccine that if it goes above a certain temper sure that the paint stays warm so unlike the hot wheels that go back the paint it's a thermal it's a thermophilic paint so once it gets warm it changes color and so if it the cold chain has been maintained the label will be one color but if it gets to where it's going and the it's the label has changed color that people know it's not good and they know not to use it so before that time if there was any thought that the cold chain might have been interrupted the vaccine had to be thrown away because there was a chance it wasn't good but with this special paint on the labels now one can confirm whether or not the cold chain has been intact and if the vaccine is good so who would ever think that that would actually influence vaccine development so there are all kinds of issues with how to Co formulate the vaccines in terms of the salts that they're dissolved in in terms of the volume so they don't precipitate so they don't react with each other that other scientists have spent devoted their lives to which frankly are outside the scope of our expertise and outside the scope of this lecture but it's that area that has allowed the Co formulation of the vaccines now there's another question that that raises and that's the issue of immune competition people have argued that if you give too many vaccines on a given day that they're gonna compete with each other and you're not gonna make a good immune response so that's basically why you can get a DTP vaccine all at the same time but you can't get an influenza vaccine add something else the same time well that's actually for other other reasons that's medical reasons but it turns out you probably can get all those vaccines and your dendritic cells you've got enough dendritic cells to see them all and orchestrate the response there there are other reasons why they don't give the flu and it has to do with people just the reaction the reaction is to me and people getting sick after the vaccines thank you little kids when they go to their pediatricians they receive a lot of shots all together and then they can manage it's also about vaccines I was just wondering like what it takes to completely eradicate like a disease like you mentioned smallpox like that vaccine eradicated smallpox but they're still polio and like chickenpox and everything like what would it take to get rid of like that so for eradication to occur the first condition that has to be met is there has to be no non-human host so the reason that smallpox can be eradicated was eradicated and the reason that polio can be eradicated as no other animal gets it so flu for instance which is carried by birds and by pigs well with current technology and currently the way these things is not it's not susceptible to eradication because there's no way we can't vaccinate all the people there's no way you can vaccinate all the birds birds fly in flocks that are wild and nobody's gonna be able to go out throughout the entire world and vaccinate all the birds that can potentially get in carry influenza but polio is another disease with no non-human reservoir so that can be eradicated you have to have a very good vaccine but then as marina talked about it has to do with being able to get to the places where the you have to monitor where the diseases are and then get to the places and vaccinate not all the only all of the people who have the disease but all of the people who are susceptible to the disease so there is a wonderful book D H Henderson was the person who led the eradication of smallpox effort I mean he wrote a wonderful memoir about it and he developed a methodology again this is a public health methodology of ring vaccination and that was its thought that's what allowed the eradication of smallpox and it's that same strategy that's been employed for polio come on down next hi I was just wondering like in terms of like allergies like a food allergy really good animals stay or like even mosquito bites like why is there no permanent memory cells that can like block you from getting an infection or like inflammation I'm so for allergy you have memory allergy is mediated by a special subtype of antibody so I didn't go into it but there are five subclasses of antibody IgG is the most common there's IgG IgA IgM which is a pentamer IgD which is fairly rare and then IgE and IgE mediates allergy and it causes mast cells to release histamine which is how one causes the allergic reaction so you do have memory for that what immunotherapy for allergy so shots tried to create I guess other enough other antibodies of other subclasses that kind of dilute that out and that also relies on memory is that what like an EpiPen is like for people who know an EpiPen is to treat the actual allergic response so once the IgE causes the mast cells to remember those were all the way on the left they've got a lot of granules they have histamine in those granules granules the granules release histamine and then that causes the problems with the airway and epinephrine the EpiPen fights that and come on down for people who get transplants how do the immunosuppressants serve decrease the response from the dendritic cells so it there are a variety of different kinds of immunosuppressants steroids which are the most general kinds don't specifically work on dendritic cells they work more on the T cells and the B cells there are newer more specific immunotherapies that are in development some of which work on dendritic cells and a colleague of a friend and colleague of ours here named Dana orange is working on one called tacrolimus which is I'm trying to remember the creature from which it's derived it's derived from a sea creature and that has a specific effect on T cells and dendritic cells I think that's an area of ongoing discovery and a good place to work and a question about the pathogens that stay dormant in the body they can also stay in the brain cells - does it clog the communication between the dendritic cells and the lymphatic cells and is there a way to prevent the viruses are to bring them out of their Latin stage so the virus can the medicine can detect them it's it's interesting that you ask that so this is actually something that you so she's just she's asking how can we get it a virus out of their latency so that the immune system can then see the virus and fight and then finally get rid of it right so so this is something that people talk about in in HIV for example so with HIV we have medications and then they don't get rid of the virus completely but they keep the virus in check so you don't see don't you no longer have the taxable circulating virus but those so but there are certainly infected cells so there are some people that think that perhaps if you take people off therapy the virus would start again dividing and then if you then came with a great vaccine or even more positive treatment you could then eliminate the virus but this is always still very experimental and I don't know if we have those tools for all the viruses right - I'm only familiar with doing it in HIV but it's an ongoing area to think about about how both to get it to come out how to get it out of the reservoir clear and then had to clear it and to prevent it from going back into the reservoir both all of those are challenges but I think that one thing that it's really hard to understand is that we we've have been exposed to a lot of viruses so probably a lot of us have had EBV maybe we had CMV chickenpox and we live so for certain factions the immune system can completely eradicate the virus clear the virus but for others the immune system keeps the virus in check so we have the virus there but it's never allowed to grow out of proportion to cause disease so that's why for example when people that have cancer they go Serena therapy and the immune systems are go to chemotherapy the immune systems are very weakened so for example if you had herpes and then that didn't really cause you trouble for many many years once you have chemotherapy and you mean system is so weak that virus is then allowed to multiply again and then cause disease so so it is interesting to think how we have all this latent viruses that we live with every day is also affect the communication of the dendritic cells with the immune system or yes because by being latent so the cells are affected but it's not a productive affection so the cell is not really presenting on its surface the antigen so the dendritic cell doesn't see it and therefore cannot kill that to the affected cell and present a little to the rest of the immune system it just stays inside not seen from what I understand dr. Steinman had pancreatic cancer and he did try to treat himself with these dendritic cells how correct of mine saying that and did he try to generate these cells ex vivo or did he try to formulate an adjuvant so that he could deliver it to his cells directly we are actually gonna talk about that at the very end so I will talk about that a little bit at the very end but there was an article that just appeared it's in the January issue of Scientific American that goes into that in a fair amount of detail so I'm going to speak in general terms at the very end but if you want the more detailed that's Katie Harman is the author of the article and it's available online currently thank you you can come down and get a flashlight my question concerns the function of the dendritic cells now you talk about how they process and present the antigens to the lymphocytes but how do they actually process those antigens like what is different between antigen that's first presented that dendritic cell compared to that antidotes presented to the lymphocyte so what actually occurs in the dendrites so so what what where we have a picture of it so what makes dendritic cells special among other things is within the cytoplasm they have a series of organelles that allow them to pick up at the surface an antigen say we could talk about HIV assuming that it worked for HIV pick up the whole virus and then they shovel the virus through a variety of endosomal compartments that are that are variously acidified that break down part of the virus and then we shutting up parts of it and and how those parts get determined is again part of the magic of dendritic cells together with molecules from the major histocompatibility complex which in humans is called HLA and then are displayed on the surface of the cell so they goes through a series of vacuoles and end acidic compartments and the details of that are beyond the scope of this lecture but it's in several of the there are good review articles which we've provided your references to exactly what the names of the compartments are and the enzymes involved in printing them apart and then putting them back together with the HLA on the surface thank you my questions about the antibodies over someone's lifespan you're exposed to a lot of diseases and pathogens and you and your body forms antibodies to fight them off is your body store these and antibodies and if so how and where does they store them but or does it does the cells just remember how to make the antibodies and they produce them when they suppose which of these is the correct way right it's more the latter so again like with t-cells the the whole trick with b-cells is memory so you get Brett you get memory b-cells which reside in the bone marrow and rest and then when the the organism the bacteria the virus or the pollen or whatever it is comes in again then they very quickly replicate divided and start pumping out active and so the best example of that that I know of is yellow fever so I'm trying to remember the exact dates but long before people were able to even interrogate the cellular arm of the immune system there was a wonderful study done in Norfolk Virginia with yellow fever so yellow fever now is a rare tropical disease but it used to be endemic throughout the eastern United States and there was a yellow fever epidemic and I may have the dates of this wrong I think it's like 1894 and then there was no yellow fever in this town at all until the 1930s and in the 1930s there was another epidemic and what it turned out was that the people who had lived through the epidemic in 1894 mounted an antibody response because they were able to draw blood and detect antibody at that point in 1930 whatever it was so these were people who who you know it lived a whole lifetime had maybe not even gotten the disease but had been exposed to it made an antibody response and then a lifetime later when we exposed to that same back same virus mounted a robust antibody response and that's because they had resting memory B cells in their bone marrow all that time it wasn't that they had circulating antibody to yellow fever for their whole life but it can be both though right so you can have circling antibodies but also have some fun memory storage absolutely and again it depends on how much antigen you're exposed to and how much time has passed so my questions about allergy medications I was wondering why the largest like side effect that we hear about with antihistamines is drowsiness rather than a compromised immune system like I'm like I get that allergies are an overreaction to like certain allergens but why when you treat them don't you stop the rest of your immune system from working because an antihistamine is only blocking the histamine molecule which is the final release product from the mast so it's not interfering with the immune response at all it's only so you're making the immune response you're making IgE and IgE is triggering the mast cell the mast cell is releasing the histamine and so the antihistamine is blocking the action of the antihistamine so it isn't impairing the immune system why antihistamines are sedating I don't know do you know sorry can't help you but you can still come down my question is what causes the Dondre cells to take its characteristic shape why they have their characteristic shape that's a very good question and I don't know the answer to that um I assume it's it's probably some sort of filaments some sort of integrins and and microfilaments are what give all cells there their shape and their structure but the specifics of it fruit dendritic cells I don't know so you can definitely come down if you have a question we can't answer and one of the videos dr. Steinman mentioned that your immune system could recognize a cell as a cancer cell because of certain imbalances within the cell so um I'm not exactly sure how a dendritic cell which recognizes antigens due to uptake receptors would be able to recognize a cancer cell is not a normal cell so it has been mutated so either it has an excess of a certain protein or it has new antigen it has developed new proteins that are foreign to to the body so so that's why they so then it enters that world of being foreign and therefore the vineyard Excel can recognize and then fight it so we have one more plush toy left which is gangrene but Clostridium but you might have noticed that most of us are wearing these buttons dr. Simon's family had made which have an image from the dendritic and an image of the dendritic cell from the first publication in 1973 so they had very generously contributed the buttons for the last few questions because we ran out of plush toys hi so why did it take so long for dendritic cells to be accepted in the scientific community has its own men today like what was the reason for the skepticism very good question why did it take so long and there are there are several reasons the first one is scientists are like everybody else and we like to think we know what we know and so there was dogma and there was evidence and people had their beliefs so that's the sort of superficial answer but then there were some other technical technical reasons so how I guess the the maybe the more important question asked is how does change happen in a scientific community so somebody has an idea they published their idea they published their data and then other people replicate their data so the most important thing in one of the most important things in science is that you can do it and somebody else can do it too so if I do a set of experiments and I say I've reached conclusion X and somebody on the other side of the globe who doesn't know me does the same set of experiments or a similar set of experiments and comes to a similar conclusion then you start to really believe that somebody that there's truth in the result because people do experiments all the time that just are wrong or what's called an artifact which is just somehow has something to do with the system and isn't really about the truth so dendritic cells were tremendously hard to work with they were those of us there are some of us sitting here not just me but others who worked with them in the beginning they were they were the very rare there very few of them I mean they're very potent they are post-mitotic so they like to die they don't ever divide so if you work with T cells or B cells they divide so if you start with a hundred you have a thousand in a couple of days but then drit excels you only ever get less so they they're very rare they're hard to get out they and they like to die and so it wasn't as though a lot of people wanted to start to try to replicate the experiments because they were so hard to do so that was one of the issues so one of the reasons one of the ways they got accepted was when the technologies were developed so they became easier to work with more people started to work with them because they were conceptually interesting even at the beginning and I think that had a lot to do with with the slow acceptance of them so I think that those would be the two reasons I don't think that's but you can come down and get a dendritic cell pen and one of the videos showed that the HIV virus enters the dendritic cell and it transfers the AIDS virus to all the other cells so if the vaccine was created would that mean potentially like destroying some of our dendritic cells yes it probably would and probably vaccines that work for other pathogens for other infections destroy infected dendritic cells all the time so one of the things that we didn't really have time to talk about today and there are hundreds or thousands of though about dendritic cells is not only do dendritic cells fight viruses but dendritic cells can also act as the reservoir for viruses and they act as the reservoir for viruses for many viruses including HIV so there is no doubt that when they become infected so an another virus they act as a reservoir for is a virus called the dengue virus and that's a virus that people get better from so there's no doubt when somebody gets infected that some of the dendritic cells that become infected get eliminated and that would likely be the case if you had a vaccine that worked as well but that has to depend on the vaccine so I talked a lot about this live attenuated vaccines that have the entire microbe so so those vaccines are able to infect and replicate for HIV that wouldn't be safe for the reason that you pointed out that the HIV would integrate into the cell and then if that produces a productive infection then the person would then become HIV infected so it can't be done for HIV what can be done is to just get pieces of HIV that cannot assemble and then make it a virus and then just show to the dendritic some of these pieces that will never become a virus that will never be able to infect would it be possible to take antibodies that were made in a lab or from from an animal that were specific against the pathogen put them inside the body and suppress the immune system so they don't attack these these new antibodies and use this to treat different pathogens such as rabies that's done that's called um passive immuno therapy so we've been talking about active vaccination where you give an agent and you get antibody made by the body but passive immunotherapy is you use fairly commonly for hepatitis B for rabies and it's it's being investigated for HIV so yes it's possible and it's being done I have to I have two questions my first is related to superbugs how do superbugs like Staphylococcus aureus resist the immune system and is that related to the mechanisms of dendritic cells so our immune systems are putting a lot of pressure into bacteria so they're always mutating so they're always so our body learns how to fight one structure of the bacteria then the bacteria evolves to modify that structure so it can no longer be seen so that's how super so by poor use of antibiotics for example you kill some bacteria but select the ones that had there are no longer sensitive to that antibiotic so so bite so and the same thing can happen to the to the immune system for instance so by modifying their structures they no longer can be seen does it make sense so that's how we call superbugs they're superbugs some superbugs are really super they are more virulent but some of them present before Mrs a MRIs a stands for methicillin-resistant Staph aureus so it's it's a step far as it has become resistant to penicillin so that mrs a is actually less virulent less powerful than MSS a but the reason we call it super bug is because not every antibiotic works against it so sometimes a mutation makes the bacteria weaker but that can still cause disease because we don't know how to fight it thank you and my second question concerns stimulating a t-cell response as I understand it there are many different types of t-cell response and I've heard that there are some negative effects of a th one mediated response and how does a th1 response differ from a th2 response so th1 and th2 refer to the the sort of skewing of the immune response and in fact it's we think of th2 as being the one that's less desirable for our kind of vaccine so th2 is more on the antibody side and th1 and it refers to T helper 1 or T helper 2 is more on the cell selves your cellular immune side and they're characterized by different cytokines which are associated with them the manufacturer but I think again that's beyond the scope of what we're discussing today but I don't think one can be thought of as good or one thought part of his bad it depends on what you're trying to accomplish they both are important in their in their own way that it's bad as if you have an exaggerated immune response be th one or th - what balance so you wanted to have enough but not too much because I don't if you remember the slide that I showed did Polly I see people got their arms read and then if that would have been a little stronger they they could have had fevers because the immune responses are induced in secretion of cytokines and these cytokines can have many effects including fever they can lead to drop in blood pressures so that's why everything has to be in balance thank you very much okay yes hi um once a dead cell catches a antigen and it shows it to this T cells and the B cells does the den trick so they get the shorter can it be reused no the dendritic cells are not ever reused that's a very good point and that's again one of the reasons they've been so hard to work with is because they they go on and they die typically by something called apoptosis which is programmed cell death so they show once they show right once they do their thing they're done is there such thing as a defective denon genetic or in excel and if so is that diagnosed yet as an illness guess actually there are there are defects in dendritic cells there are there's a disease called histiocytosis X um and there's a whole group of diseases that are referred to as the histiocytosis dendritic cells and macrophages used to be called histiocytes where there are tumors of these cells and those have been described for a long time probably since I don't know the certainly since the 50s but maybe since the 30s but this year a colleague of ours here the Rockefeller genre Casanova described a primary dendritic cell defect associated I believe and I could be mistaken about this with il8 that was published in the New England Journal of Medicine yes yes they have been described they're extremely rare though why are certain diseases found in like specific age groups does that have to do with the dendritic cell why specific diseases are found in specific a terms I don't think that's specifically related to Denver at least that I'm aware of but come get a button anyway okay hi so I wanted to know like I have a few questions like for viruses like HIV that like rapidly mutate when like creating a vaccine like if it's different so that it's not as effective as it was like the first time how you're saying like how viruses or bacteria become immune to like certain defenses in the body so is it possible that there's a specific target you can use that never changes it's why like you can say okay so this virus does this so if we target that if the virus were to change will be a completely different virus and then like well if you want to answer that one because I have other questions so there with any virus particularly with HIV there are lots of parts of the viruses that change a lot but then there are parts that are what's called conserved and change very little and so we target our vaccines to the conserved portions exactly for the reasons that you mentioned the vaccine that we're working on is targeted to a highly conserved portion so it's the same in viruses that can differ up to 30% in some portions the portion the center portion called gag that we're working with is highly conserved and you talked about how the dendrites teach the immune system how to defend against these things so does the dendrite teach only one thing or do they can they teach multiple things so when it's a single dendritic cell presents a single set of antigens but when you have a population of dendritic cells they can teach multiple things okay and if they you say the dendritic cells die after they you know do their job what is it so it's safe to say that if you do have a vaccine that may be as act as a reservoir for like HIV or other viruses wouldn't the cells just die off and the virus also die with the dendritic cells I'm sorry I didn't I didn't hear it the last part okay so if this dendritic cells die after taking in the virus or whatever they're looking for is it after they die the whatever they take in it's no longer harmful to the body right right that's right except for the fact the the problem with that is T cells which also Harbor HIV are dividing so if the is that energetic cells were in isolation it wouldn't be a problem but because there are other cells that are dividing rapidly the virus is being propagated all right Thank You K come down last one over here Shin that refers back to in the earlier slide you talked about how now originally or is a model of like the dendritic cell being like a commander for the army but now it's more like like the conductor in an orchestra and that there they've actually discovered that there are multiple types of dendritic cells could you explain a little bit more about what the significance of the differences between those two models are in the differences between the different dendritic cells and maybe give a few examples well I think that the the first example is in the beginning it was thought that like the cartoon showed that dendritic cells talked or instructed only T cells Ralph's initial work was on the interaction of dendritic cells and T cells so that was a good analogy for the army you had the commanders and the soldiers but it turns out as we showed you the dendritic cells talk and teach not just the the T cells but the B cells the NK cells the NKT cells so that's much more like an orchestra okay you think that there are more discoveries to make about the actual like knowledge of what these dendritic cells are and like for example whether like art is there anyone trying to see if they can extend the lives of dendritic cells so that they don't just die immediately or do you think now the significance of dr. Steinman's discovery is that now it can be used to make all these different immunity well I said I think that the significant both are correct so the significant is significance is that they can be used but there is always more to learn there are so many discoveries to be made we can't even imagine what they all are and that's part of the the most wonderful perhaps the most wonderful part of doing this work you can only imagine so far and the work goes beyond it so yes there are all sorts of like there are countless discoveries to be made about dendritic cells and you guys are going to be the ones to make them not us I mean maybe we'll make a few more but it'll be up to you but the I think the importance of the discovery that they can be used stands on its own there is anyone trying to extend the lives of the dendritic cells or all that not a focus in the research right not that I'm aware of but that doesn't mean it's not happening okay okay thank you you're welcome come down and get a button our last two questions fiers has changed a lot so does that mean that dendritic cell evolves with the virus or does it just um I wouldn't say that the dendritic cell evolves with the virus the immune response involves with the virus so remember you when you think about it genetic so there's a single dendritic cell and then there populations of dendritic cells so any single dendritic cell isn't going to change much with the virus but the populations will as the virus changes the dendritic cells responding to it is a group will change but really the dendritic cell doesn't keep a memory of the virus so the T cells and the B cells are the ones that need to learn so the dendritic cells will always present detect that foreign material that it's coming in but the the T cells and that the B cells are the ones are going to change over time because they're gonna be seeing different presented antigens so they're the ones are constantly evolving as the virus constantly about so for example if you get someone with HIV that person has if that person has ongoing HIV replication you're gonna have groups of T cells that recognize gag there are other groups of T cells that recognize envelope and as envelope changes you're gonna get more and more different types of T cells but for some reason in HIV they're always falling behind the virus is always ahead them it's always changing quicker the Linnaean system can keep up with but not the didn't read Excel necessarily all right our last question yeah so my question is if vaccines are designed to use to boost and immune system response here me hypothetically use it to boost an old person's immune system and those live better does live longer I'm sorry I'm sorry you have to say I couldn't hear what you said if vaccines are designed to boost an immune response can we habitat hopefully use it to boost an old person's immune system and does live longer to be so so a lot of old people they've had chicken pox and then they've been able to chicken pox virus chicken the varicella virus is steven their body's in there in the neurons but the immune system is keeping them in check as you got older your immune system is weakened and then some of that virus can then replicate and then you have what's called shingles so now recently a few years ago they have a shingles vaccine and that is exactly the purpose of the vaccine to give a boost to the immune system so that they can again have more memory cells they can again control the varicella virus how did dendritic cells get their names and do they have any relation to dendrites from their name so I think I mentioned earlier on dendritic cells got their name because they had tree like prozac projections and it's very confusing because there are dendrites in the brain that also have tree like projections but other than the fact that they both look like trees and then they're both cells that's kind of about it so that's that's they're not related otherwise okay so now thank you all for your questions and come get your pen and thank you no we're not done we're not done we're not about two minutes and we're done okay we'll go anyway so the best but the best part is to come so so as was alluded to earlier at the end of dr. Steinman's life he had pancreatic cancer and he decided to use his dendritic cells to help fight his panther which was I think what he regarded as the experiment of his life the details of this are are described pretty pretty good detail in this article that just appeared in Scientific American so if anybody is interested I suggest that you go and read the article this is picture the dendritic cell the work was Ralph's work but obviously was done by lots of people and so these are the people who were there at the beginning and through the middle and did the work that you saw Maggie Whitmer pack is here today and she's also the kind source of all those wonderful plush toys Michelle Michelle messin swag is as was mentioned gave Ralph's novella dress and he's our new lab head and though he's not here I think his kids are here so I think they're probably hiding in the back I'm not sure that any of the rest of these people are here but maybe they're here in spirit with us and this is art this is our current lab picture or the most recent one that was taken about three years ago and I don't know if you can see Ralph we don't have one of those cool little circle things like we did on the other but there he is for this lab this was on the steps of our Hospital and this is all of the people in our lab currently whose work you saw in pieces in parts this is all of our clinical studies are done here at the Rockefeller University Hospital our volunteers Zach via in a public Ferris helped us put the lecture together and Gloria has run this lovely event for all of us and as you know Mary Jean introduced us but this is the best part so hold on okay so now marina up here so Ralph didn't get to wait wait it did not get to accept the Nobel but he did get to accept the last girl ward so ladies and gentlemen Alaska award is exhilarating for the recipient scientists lab and institution in fact I'm so excited that I'm actually feeling dendritic wanting to embrace in my processes all the members of the jury and the friends and family are here today thank you all for coming and Happy New Year I forgot the best part so the future relies with you and other very young scientists and you met Ralph's granddaughters at the beginning but this is Ralph's grandson who's a little young for the lab but we hold out great hopes so happy new year csi syndrome dissertation Brooklyn campus.

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