The hypothesis that the pancreatic beta cell is a primary site of pathology in human and experimental diabetes, and the knowledge that the beta cell population is affected by genetic background and response to immunologic injury, has directed our attention to the need for further study of spontaneous animal models of Type l autoimmune diabetes. This request is for continued support of research projects designed to study the pathogenesis of diabetes in the unique model of insulin dependent diabetes, the Biobreeding/Worcester (BB/Wor) rat. The mechanism of Kilham rat virus (KRV) induced diabetes in BB/Wor diabetes resistant (DR) and other inbred rats will be studied using cellular immunology, molecular virology and immunocytochemistry. We will: * Test the hypothesis that KRV activates autoreactive effector cells. * Identify the phenotype of the diabetogenic effector cells. * Evaluate molecular mimicry as a model for diabetes induction. * Examine the role of beta-cell secretory activity in susceptibility to virus-induce diabetes. The research colony of BB/Wor rats will continue to be inbred and serve as the world's reference colony of this model of autoimmune diabetes. Virtually all of the proposed experiments are immunopathologic in nature. As such, they incorporate morphologic, cellular immunology, and molecular readout systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK019155-22
Application #
2391307
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Akolkar, Beena
Project Start
1977-09-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
22
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Ellerman, K E; Like, A A (2000) Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats. Diabetologia 43:890-8
Ellerman, K E; Like, A A (1999) Islet cell membrane antigens activate diabetogenic CD4+ T-cells in the BB/Wor rat. Diabetes 48:975-82
Ellerman, K E; Richards, C A; Guberski, D L et al. (1996) Kilham rat triggers T-cell-dependent autoimmune diabetes in multiple strains of rat. Diabetes 45:557-62
Ellerman, K E; Like, A A (1995) A major histocompatibility complex class II restriction for BioBreeding/Worcester diabetes-inducing T cells. J Exp Med 182:923-30
Stubbs, M; Guberski, D L; Like, A A (1994) Preservation of GLUT 2 expression in islet beta cells of Kilham rat virus (KRV)-infected diabetes-resistant BB/Wor rats. Diabetologia 37:1186-94
Guberski, D L; Butler, L; Manzi, S M et al. (1993) The BBZ/Wor rat: clinical characteristics of the diabetic syndrome. Diabetologia 36:912-9
Ellerman, K; Wrobleski, M; Rabinovitch, A et al. (1993) Natural killer cell depletion and diabetes mellitus in the BB/Wor rat (revisited). Diabetologia 36:596-601
Brown, D W; Welsh, R M; Like, A A (1993) Infection of peripancreatic lymph nodes but not islets precedes Kilham rat virus-induced diabetes in BB/Wor rats. J Virol 67:5873-8
Barlow, A K; Like, A A (1992) Anti-CD2 monoclonal antibodies prevent spontaneous and adoptive transfer of diabetes in the BB/Wor rat. Am J Pathol 141:1043-51
Like, A A; Guberski, D L; Butler, L (1991) Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats. Diabetes 40:259-62

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