The BB rat develops an autoimmune insulin dependent diabetes mellitus (IDDM) that closely resembles human IDDM. However, little is know about the predisposing abnormalities that lead to diabetes, or about the initiating factors that result in the autoimmune destruction of insulin-producing beta cells. The present proposal is designed to test the hypothesis that T cell abnormalities that lead to IDDM in BB rats result from defects in the development of prothymocytes and/or their differentiation in the thymus. Our working model to test this hypothesis is that two T cell developmental defects have occurred in diabetes-prones BB (DP) rats: 1) The generation of autoreactive diabetes effectors T cells; 2) the inability to generate RT6+ regulatory T cells. We believe that the relative balance of diabetes effector and regulatory T cells is an important factor in ultimately determining susceptibility or resistance to IDDM.
Specific Aim 1 will identify and characterize the predisposing factors important in the susceptibility of DP rats to IDDM. We will determine the role of intrinsic versus cells or lack or regulatory RT6+ T cells. The stage of T cell development (prethymic, intrathymic, postthymic) and the cellular and/or environmental mechanism(s) that result in T cell developmental defects will be determined.
Specific Aim 2 will investigate the initiating factors important in the pathogenesis of IDDM. A lymphocyte transfusion model of protection of DP rats will used to study the role(s) of regulatory (RT6+) T cells in preventing diabetes. A novel model IDDM, the RT6-depleted diabetes resistant BB (DR) rat that """"""""spontaneously"""""""" develops diabetes, will be used to investigate the autoimmune effector mechanisms that mediate destruction of beta cells. We will compare the effector and regulatory mechanism(s) that induce or prevent diabetes in DP and RT6-depleted DR rate to determine whether they are the same or different. Our ultimate goal is to understand both the predisposing and initiating factors important in the pathogenesis of IDDM in BB rats. These experiments should allow us to test our hypothesis, and to formulate possible therapeutic modalities for the treatment of human IDDM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK036024-07
Application #
3234343
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1989-04-01
Project End
1994-03-31
Budget Start
1991-07-15
Budget End
1992-03-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Mordes, John P; Cort, Laura; Norowski, Elaine et al. (2009) Analysis of the rat Iddm14 diabetes susceptibility locus in multiple rat strains: identification of a susceptibility haplotype in the Tcrb-V locus. Mamm Genome 20:162-9
Zipris, Danny; Lien, Egil; Nair, Anjali et al. (2007) TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat. J Immunol 178:693-701
Blankenhorn, Elizabeth P; Descipio, Cheryl; Rodemich, Lucy et al. (2007) Refinement of the Iddm4 diabetes susceptibility locus reveals TCRVbeta4 as a candidate gene. Ann N Y Acad Sci 1103:128-31
Morrison, Alan R; Moss, Joel; Stevens, Linda A et al. (2006) ART2, a T cell surface mono-ADP-ribosyltransferase, generates extracellular poly(ADP-ribose). J Biol Chem 281:33363-72
Beaudette-Zlatanova, B C; Whalen, B; Zipris, D et al. (2006) Costimulation and autoimmune diabetes in BB rats. Am J Transplant 6:894-902
Hillebrands, Jan-Luuk; Whalen, Barbara; Visser, Jeroen T J et al. (2006) A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3. J Immunol 177:7820-32
Zipris, Danny; Lien, Egil; Xie, Jenny X et al. (2005) TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol 174:131-42
Todd, Derrick J; Forsberg, Eric M; Greiner, Dale L et al. (2004) Deficiencies in gut NK cell number and function precede diabetes onset in BB rats. J Immunol 172:5356-62
Hornum, Lars; DeScipio, Cheryl; Markholst, Helle et al. (2004) Comparative mapping of rat Iddm4 to segments on HSA7 and MMU6. Mamm Genome 15:53-61
Mordes, John P; Bortell, Rita; Blankenhorn, Elizabeth P et al. (2004) Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J 45:278-91

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