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.
| 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 |
