While certain MHC class II molecules clearly contribute to type 1 diabetes (IDDM), there is increasing evidence some MHC class I molecules also play an essential pathogenic role. This is partially demonstrated by the fact that the common K/d and/or D/b molecules expressed by NOD mice mediate T cell responses necessary for IDDM development. Similarly, evidence suggests that the risk of IDDM development in humans is increased when certain MHC class I variants, including HLA-A2, are expressed in conjunction with particular MHC class II susceptibility alleles. In an effort to address the role of human MHC class I genes in conferring susceptibility or resistance to IDDM, I will employ NOD mice transgenically expressing human class I genes, HLA-A2.1 or HLA-B27. While the HLA-A2.1 transgenic mice are diabetes susceptible (95 percent incidence in females by 30 weeks of age), the HLA-B27 transgenic mice are resistant to the development of diabetes (25 percent incidence in females by 30 weeks of age).
The specific aims of this project are to (1) determine if transgenically expressed human HLA-B27 MHC class I molecules inhibit IDDM development in NOD mice by blocking the development of B cell autoreactive T cells; and (2) determine if transgenically expressed human HLA-2. 1 MHC class I molecules mediate diabetogenic CD8 T cell responses in NOD mice, and if so identify mechanisms controlling development of these effectors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK059717-03
Application #
6712085
Study Section
Special Emphasis Panel (ZRG1-IMB (20))
Program Officer
Hyde, James F
Project Start
2002-05-01
Project End
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
3
Fiscal Year
2003
Total Cost
$49,864
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Marron, Michele P; Graser, Robert T; Chapman, Harold D et al. (2002) Functional evidence for the mediation of diabetogenic T cell responses by HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice. Proc Natl Acad Sci U S A 99:13753-8