Abstract

This project sets out to test two hypotheses: (1) Immunologically mediated diabetes in the NOD mouse results from CD4 T cell- dependent inflammatory tissue damage. The proximate cause of diabetes is free-radical mediated beta cell damage. We test hypothesis (1) by determining the phenotype of cells responsible for the transfer of the disease to non-diabetic NOD mice, and disease recurrance in islet tissue transplanted to diabetic NOD recipients. Confirmation of involvement in the disease process comes from in vivo biological studies of T cell lines and clones, derived from diabetic NOD mice. The mechanism of islet damage will be approached by investigating implications of the Okamoto model for inflammatory islet damage. This model postulates that damage results from free-radical production in the region of the beta cell. These radicals cause DNA breaks, which in turn activate a DNA repair enzyme and result in a depletion of NAD levels in the cell. As a result proinsulin synthesis in inhibited and the beta cell becomes even more sensitive to radical damage.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK040144-04
Application #
3855141
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Peterson, J D; Haskins, K (1996) Transfer of diabetes in the NOD-scid mouse by CD4 T-cell clones. Differential requirement for CD8 T-cells. Diabetes 45:328-36
Sellins, K S; Gold, D P; Bellgrau, D (1996) Resistance to tolerance induction in the diabetes-prone biobreeding rat as one manifestation of abnormal responses to superantigens. Diabetologia 39:28-36
Gold, D P; Shaikewitz, S T; Mueller, D et al. (1995) T cells from BB-DP rats show a unique cytokine mRNA profile associated with the IDDM1 susceptibility gene, Lyp. Autoimmunity 22:149-61
Peterson, J D; Pike, B; Dallas-Pedretti, A et al. (1995) Induction of diabetes with islet-specific T-cell clones is age dependent. Immunology 85:455-60
Bergman, B; Haskins, K (1994) Islet-specific T-cell clones from the NOD mouse respond to beta-granule antigen. Diabetes 43:197-203
Peterson, J D; Pike, B; McDuffie, M et al. (1994) Islet-specific T cell clones transfer diabetes to nonobese diabetic (NOD) F1 mice. J Immunol 153:2800-6
Bellgrau, D; Redd, J M; Sellins, K S (1994) Peculiar T-cell signaling does not preclude positive selection in the diabetes-prone BB rat. Diabetes 43:47-52
Shehadeh, N N; Gill, R G; Lafferty, K J (1993) Mechanism of self-tolerance to endocrine tissue. Springer Semin Immunopathol 14:203-20
Hayward, A R; Shriber, M; Cooke, A et al. (1993) Prevention of diabetes but not insulitis in NOD mice injected with antibody to CD4. J Autoimmun 6:301-10
Shehadeh, N N; LaRosa, F; Lafferty, K J (1993) Altered cytokine activity in adjuvant inhibition of autoimmune diabetes. J Autoimmun 6:291-300

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