 All right, while we're switching computers here, I'd like to introduce Ed Engelman, Professor of Pathology and Medicine, Immunology and Rheumatology, Director of the Stanford Blood Center, which is one of the only university-based blood centers in the country. And this comes with a great story about Ed initiating the testing of blood donations for HIV at a time 30 years ago when this was considered a great and unnecessary imposition. And it's pretty obvious now how that story turned out. He may actually be better known for his work on the first vaccine to be approved by the FDA for the treatment of cancer just last year. And most recently, his lab has published two very high-profile studies in nature medicine, linking immunity, insulin resistance, obesity, and type 2 diabetes, which seems like a great follow-up to Gary's talk, yes? Thanks, Ed. Uh-oh. I don't know, probably not. Great. I have 30 minutes, right? Just kidding, just kidding. Christopher has been working so hard to organize this event and admonishing us to make sure we stay within our time limit, so I shouldn't have said that. Give him a heart attack. Yes, yes. Well, as Christopher mentioned, I'm actually an immunologist and really had no knowledge or business in the field of which we're discussing today. Gary's field. But a postdoc, a new postdoc of mine who came to the lab just a few years ago raised a crazy idea, which is, is it possible that the immune system plays a really important role in the diabetes that develops in association with obesity? And so I don't have to tell this group that obesity is a big problem. That's funny, I'm being the first speaker to sort of mention it, but our focus has been on the disease associations with it, in particular insulin resistance and type 2 diabetes. As I think most of you know, 25% of people over the age of 60 are obese and develop diabetes. So there's a remarkable association between these two disorders. And historically, there has been no real thought that type 2 diabetes is an immunological disease or even an inflammatory disease. Type 1 diabetes, by contrast, of course, is a classic autoimmune disease where the insulin-producing cells are attacked and destroyed by host T cells. Our recent studies suggest that the adaptive immune system, those elements of the immune system that can recognize elements with specificity play a significant role in the development of this disease. Now, most of our studies have been done in laboratory animals, animal models, particularly fat mice, but not all. And I know Jerry will remind me that most of these studies have been done in mice and not people, and I think that's a fair point. But it's really easy to make mice fat. You just give them a high-calorie, high-fat diet, and those animals invariably develop insulin resistance and go on to become diabetic, basically indistinguishable from people. So that's what we started doing. We took C57 black mice, which is a normal mouse strain, gave them a high-fat, high-calorie diet, and started studying their adipose tissue. And what we discovered is that in their adipose tissue, in the deep adipose tissue or visceral fat, more so than the subcutaneous fat, we found changes. We found massive infiltrates of inflammatory adaptive immune cells, particularly T cells, and I don't have the time today to demonstrate all the data, but I will simply point out that one particular subset of T cells called T regulatory cells which down-regulate the immune response are present in much lower proportions in the visceral fat of these obese mice than they are in normal mice. And in fact, other cells, particularly inflammatory T cells, TH1 cells and TH17 cells, which produce potent inflammatory cytokines are present in much higher proportions than they are in normal animals. So about three years ago, we started experiments based on the hypothesis that the inflammatory T cells were bad, and what would happen if we gave an antibody that would eliminate these cells or at least eliminate some of them? And the classic antibody that is used, we use for these studies, is a broad-based anti-CD3 antibody that affects all T cells, and generally eliminates more of the inflammatory T cells than the T-reg cells, and that's what we did. So we took these animals, gave them a few injections of this antibody over a period of a few days, and then observed them over a period of several months, and what we found is that the proportion of regulatory T cells that don't have a pointer that works, so I will just point with my finger. After anti-CD3 treatment, you'll see in the vat, in the visceral fat, goes from about 8% to about 17.7%. And none of the controls showed any problems, so we were able to reconstitute the normal ratio of T cell subsets after this antibody treatment, and the most striking finding is that glucose, the abnormalities of glucose metabolism completely normalized in these animals, and this was part of the basis for our first paper in Nature Medicine, which was published in 2009, which documented that the adaptive immune arm, particularly T cells, played a critical role in development, and as I said, it's remarkable that essentially a single course of treatment with this antibody normalized the glucose metabolism of these animals for as long as we observed the animals thereafter. Not to exclude human beings from our studies, we did have access at that time to biopsies of fat from individuals undergoing various types of surgery, and we were able to document that the body mass index was a very nice predictor of the ratio of TH1 cells to T-reg cells, so T-bet is a marker of TH1 cells, and FoxB3 is a marker of the T-reg cells. We did immunohistochemistry staining, very simple, straightforward, simply counted the various populations, and we're able to confirm that the same changes in these subsets that occur in our fat mice also occurred in obese individuals in proportion to their obesity. So just to summarize very briefly, the T cell role in glucose metabolism, what our findings indicate, and others have now added to these findings and confirmed them and extended them, is that certain subsets of T cells, notably the T-reg cells and the TH2 cells, which are immunomodulatory cells, tend to down-modulate inflammation, and under normal circumstances, at least in lean individuals, they cause macrophages to remain quiescent. These macrophages produce IL-10, which keeps the inflammation away and maintains a normal status. Under obese conditions, there is an invasion, an infiltration of inflammatory T cells, particularly TH1, TH17, CDA defector cells, that overwhelms the regulatory cells, causing these macrophages to become inflammatory, and we believe that is the essence of the inflammation that ultimately causes and exacerbates insulin resistance. Now, not to... Well, let me just say that at that point, we knew that T cells were very important. We then asked the question, what about the other very important adaptive immune cell, the B cell, the cells that produces antibody that can also produce cytokines, that can also be an antigen-presenting cell and stimulate T cells? And what we discovered in other sets of mice where we were able to knock out various types of cells and other things, is that in fact, B cells also play a very important role. So let me just show you here that if we administer to obese animals a rendered obese by a high-fat, high-calorie diet, a broad anti-B cell antibody, in this case anti-CD20, in order to eliminate all the B cells, we find that the effect we see is similar to what we saw with our broad anti-T cell antibody, namely a normalization of glucose metabolism, a reduction in inflammatory mediators and really a remarkable and surprising observation. In addition to that, we looked into the mechanisms by which these B cells are causing problems and one very important mechanism is their production of autoantibodies because we could transfer the disease, we could transfer the abnormal glucose metabolism by taking IgG from obese insulin-resistant animals concentrating the total IgG and transferring it to young, lean animals that had started a high-fat diet and we could essentially reproduce the abnormal insulin and glucose metabolism. So that is one mechanism by which B cells can induce or exacerbate disease. This is a simple summary, not so simple to you, I'm sure, but simple in that analogous to the T cell summary in that what B cells can do, they can make antibodies, we believe that these antibodies are to specific inciting antigens, but that one role that these antibodies have is to attach to the FC component of macrophages and cause those macrophages to become inflammatory. We know that B cells are also presenting antigens to T cells, the same T cells that were driving the inflammation in the visceral fat. So we believe that B cells and T cells are working together to make this disease worse. And this is a brief summary of this work. So the last piece on B cells was published in Nature Medicine about three or four months ago. And to summarize what our current state of knowledge is with regard to the role of the immune system, we know that in lean, healthy individuals, insulin sensitivity is regulated, regulated by good T lymphocytes, if you will, the cells that down modulate the immune response. Under conditions of high fat diet, there is an inflammatory reaction that occurs in adipose tissue, particularly the visceral fat, with increased frequency and activation of inflammatory T cells, TH1, TH17, CD8 cells, B cells in type one macrophages. Those are the macrophages that put out pro-inflammatory cytokines that overwhelms the normal down modulating activities of the other T cell subsets. B cells contribute to the disease by activating pro-inflammatory T cells and macrophages and producing auto-antibodies. What I didn't show you today was that in the paper that we published just a few months ago, we were able to demonstrate that with the help of Tracy McLaughlin, that in individuals who are otherwise healthy, but insulin resistant, in a small cohort of men with such characteristics, they had in their circulation, auto-antibodies that were distinct from anything that was in the insulin and otherwise BMI matched insulin sensitive individuals. So we believe we've identified, at least in a preliminary way, an auto-antibody profile that may ultimately predict the development of type two diabetes associated with obesity. Remarkably, both the T cell and B cell mediated effects are reversible as we demonstrated with antibodies to the cells, at least during the development of disease. So that's our story. I want to point out that this last several years has been a collaboration between people here at Stanford and people at the University of Toronto. Two identical twin postdocs, Dan Weiner and Sean Weiner were really played critical roles in the development of the hypothesis. Leshyn and my lab and Dan have worked very closely in all of this work and our principal collaborator here at Stanford is Tracy McLaughlin, but there are many others that have contributed to this work. And with that, I will also point out that we work over at the Stanford Blood Centre, which Christopher kindly described a few miles from here, but it's a very happy place to see all these people are smiling because they're so happy. All right, thank you. 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