Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease resulting from the T cell mediated destruction of insulin-producing beta cells located in the pancreas. Current treatment, which includes insulin replacement by injection, frequent blood glucose monitoring, and dietary/exercise discipline, can prevent death from hormonal insufficiency, but is not curative and does not prevent long-term complications. Those complications include nerve damage and vascular deterioration (large and small blood vessels) resulting in damage to various organs, including the heart, brain, kidneys, and eyes. Life expectancy is shortened by an estimated one-third compared to similar individuals but without T1DM. This work, initiated in the mid 1990's at the Naval Medical Research Institute and further developed at the University of Ulm in Germany and subsequently for the past year at the NIDDK-TAB, has characterized a unique murine model of autoimmune diabetes using rat-insulin promoter (RIP)-CD80 transgenic mice (RIP-CD80 mice). These animals are predisposed to immune mediated beta cell destruction based on their beta cell-specific expression of the costimulatory molecule CD80. While RIP-CD80 mice rarely develop spontaneous diabetes (incidence 6.7%, compared to none of wild type mice), we have observed and have initially characterized the profound susceptibility these mice display to develop progressive islet infiltration and eventually insulin dependent diabetes mellitus (IDDM) following immunization with beta cell autoantigens (i.e. protein molecules that are expressed specifically by the pancreatic beta cells of these mice). For instance, these animals, unlike non-transgenic littermates, uniformly develop islet cell destruction and IDDM upon immunization with insulin precursors, a beta cell autoantigen strongly suspected to be involved in the pathogenesis of T1DM in humans. We have shown that at least one relevant autoantigenic CTL epitope (H-2b) must be present in the mature insulin molecule, which contrast with current algorhythm-based epitope prediction models. Moreover, our model turned out to be so far amazingly predictive and much more accurate of reponses by the non-obese diabetic (NOD) mouse, a model most widely used to study autoimmune diabetes. This laboratory's objective using the above mouse model can be summarized as follows:(1) We are preparing to identify self-antigens (Ag) and CTL-epitopes thereof that are thought to be important initial target Ag for the developing autoimmune response. For this purpose, we will explore several routes of immunization of candidate auto-antigens, including peptide immunizations, DNA-vaccines, and retrovirally transduced dendritic cells (DC), for their ability to elicit (MHC class I restricted) T cell responses, insulitis, and diabetes in RIP-CD80 transgenic mice.(2) We will study beta cell specific T cell responses in an adoptive transfer model where the primary sensitization of the autoreactive T cells will take place either in vitro, or by immunizing in vivo, as proposed in (1). These studies will focus on the mechanisms of the developing beta cell destructive immune responses, as described in 1) and 2), and will attempt to identify novel therapeutic approaches to interfere with the ongoing immune responses. Finally, (3) we will continue to explore our preliminary data suggesting that non-professional antigen-presentinmg cells (APC), such pancreatic beta cells or fibroblastoid cells, can prime naive precursor CTL in vivo, and stimulate a rather chronic autoimmune response. In contrast, professional APC, derived from the haematopoetic lineage such as DC, induce a rather uniform and fulminant islet destruction and diabetes, not typically seen in human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK062002-02
Application #
6546671
Study Section
(TAB)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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