Primary attention is focused on experiments to define the immune pathogenesis of spontaneous diabetes in the BB rat, an animal model with many features in common with the human disease. Since we have found that transplanted islets succumb to the same autoimmune damage which destroys the native islets, islet grafts will be employed as a probe to investigate the phenomenon of MHC restriction in autoimmune islet damage. Employing inbred and congenic strains of rats attempts will be made to locate the region of MHC responsible for restriction phenomena. The fate of antigen presenting cell depleted islet grafts will be studied in immunologically tolerant hosts to identify and characterize the activity of effector cells involved in islet damage. Investigations are also planned to determine whether the islet damage seen in these tolerant hosts is caused by an aberrant differentiation of normal stem cells in an autoimmune milieu which results in autoreactive cells in these hosts. Examination of the role of thymic education of T cells and MHC restriction patterns of diabetogenic effector cells is a major goal of the grant. Aspects of the proposed studies which are of possible immediate practical importance are: 1) perfection of islet transplant techniques; 2) markers for prediabetic states; 3) development of safe and effective immunosuppression as treatment or prophylaxis of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK026007-16
Application #
2137816
Study Section
Special Emphasis Panel (NSS)
Project Start
1979-06-01
Project End
1995-05-31
Budget Start
1994-06-01
Budget End
1995-05-31
Support Year
16
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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DeMatteo, R P; Chu, G; Ahn, M et al. (1997) Long-lasting adenovirus transgene expression in mice through neonatal intrathymic tolerance induction without the use of immunosuppression. J Virol 71:5330-5
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Ahn, M; Chang, E; Chu, G et al. (1995) Cellular requirements for pancreatic islet xenograft rejection. Transplant Proc 27:3302-3
Markmann, J F; Desai, N M; Bassiri, H et al. (1994) Prolonged survival of class I deficient mouse islet allografts but not xenografts. Transplant Proc 26:748
Campos, L; Alfrey, E J; Posselt, A M et al. (1993) Intrathymic inoculation of donor cells promotes survival of rat orthotopic liver allografts. Transplant Proc 25:488-9
Markmann, J F; Odorico, J S; Bassiri, H et al. (1993) Deletion of donor-reactive T lymphocytes in adult mice after intrathymic inoculation with lymphoid cells. Transplantation 55:871-6;discussion 876-7
Posselt, A M; Barker, C F; Friedman, A L et al. (1993) Intrathymic inoculation of islets at birth prevents autoimmune diabetes and pancreatic insulitis in the BB rat. Transplant Proc 25:301-2

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