Program Directors: Stephen Gitelman, MD and Abul Abbas, MD
The overall objective of the UCSF DRTC Autoimmunity Program is to bring together research groups with an interest in immunology, autoimmunity and Type 1 diabetes to apply their complementary expertise to the problem of how a series of immunological events, likely superimposed on a genetically susceptible background, lead to the development of IDDM.
These events are: (1) Exposure of the immune system to islet autoantigens; (2) Failure of tolerance in islet antigen-reactive T cells; and (3) Influx of lymphocytes into islets followed by immune destruction of beta-cells.
Specific program objectives are listed below:
- Characterization of islet autoantigens and immune responses to islet antigens
Although several important islet autoantigens have been identified, very little is known about the immune responses to these antigens and the regulation of such responses. The studies in this component will focus on developing humanized mice expressing HLA molecules, in which responses to T cell epitopes involved in human disease can be examined. In addition, peptide-MHC tetramers will be used to quantitatively follow T cell expansion and function in patients, relevant controls, and animal models. Finally, many questions remain concerning the nature and basis of immunogenicity of autoantigens. How does the GAD65 epitope specificity of autoreactive B-cells affect the presentation of antigen to DR and DQ restricted T-cells in IDDM. What role do autoimmune B cells play in shaping the autoimmune DRB1*0401 restricted T cell repertoire? What other antigens are involved in the development and progression of the disease?
- Failure of T cell tolerance and regulation
The fundamental problem in diabetes (and all other autoimmune diseases) is failure of self-tolerance. The work of these investigators has been central to our current understanding of the mechanisms of tolerance, in particular the roles of T cell deletion, CTLA-4-mediated anergy, and regulatory T cells. A large number of transgenic and knockout models of autoimmunity, as well as NOD mice crossed to several knockouts, are available in these laboratories for mechanistic studies. The established collaboration between T cell biologists and biochemists studying signaling pathways promises to provide invaluable insights into the mechanisms of tolerance and how it is disrupted.
- T cell reactions in tissues
Several laboratories are focused on T cell and natural killer (NK) cell migration into tissues, and the roles of chemokines and adhesion molecules. In addition, investigators are developing sophisticated imaging techniques for following lymphocyte infiltration into tissues and the activation of lymphocytes in lymphoid organs and non-lymphoid tissues. Such studies are the key to understanding the evolution of tissue damage in immune reactions, and to developing strategies for controlling injury to tissues.
- Clinical trials and immune monitoring
Investigators will translate advances from basic science investigation into novel approaches to arrest or reverse the destruction of beta cells in human clinical trials. One paradigm for this process is the on-going work at UCSF with an anti-CD3 monoclonal antibody, hOKT3y1(ala-ala), which was developed in the laboratory of the Diabetes Center. Several clinical trials are currently underway with this agent in subjects with new onset type 1 diabetes, in an attempt to preserve endogenous insulin secretion. Another approach (spear-headed by Dr. Wofsy) has been to use co-stimulatory blockade (anti-CD40L) to abrogate disease in patients with Lupus. These reagents and others are ready for testing in both new-onset and high risk prediabetic patients. However, a critical component of these studies is to investigate the mechanism of action of this agent in vivo, and thus entails re-involvement of the basic immunologists. The basic science and translational researchers in this program work together and with industry to examine these drugs, where promising pre-clinical data are available in Type 1 Diabetes.
Program members:
| Steinunn Baekkeskov |
Jeffrey A. Bluestone |
| Juan Carlos Jaume |
Jason Cyster |
| Kevan Herold |
Matthew Krummel |
| Lewis Lanier |
Umesh Masharani |
| Martha Nolte |
Steven Rosen |
| Stephen Rosenthal |
Art Weiss |
| David Wofsy |
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