Insulin dependent diabetes mellitus (IDDM) in both humans and NOD mice is a T cell mediated autoimmune disease controlled by multiple susceptibility ( Idd) genes both inside and outside of the major histocompatibility complex (MHC). Unusual variants of MHC class II genes clearly contribute to diabetes susceptibility. However, despite the fact they represent common alleles also found in many strains lacking autoimmune proclivity, the MHC class I ene products expressed by NOD mice (e.g. Kd, Db) mediate T cell responses essential to the initiation of IDDM. The overall hypothesis to be tested in this project is that the relatively common Kd and/or Db MHC class I gene products aberrantly acquire autoimmune diabetogenic hypothesis is a stock of NOD mice transgenically expressing a T cell receptor (TCR) from Kd restricted diabetogenic T cell clone.
in aim 1, this TCR transgenic stock will be used to identify the requirements for in vivo activation of MHC class I restricted diabetogenic T cells.
Aim 2 will use the TCR transgenic stock to determine if any non-MHC class I restricted diabetogenic T cells.
Aim 2 will use the TCR transgenic stock to determine if any non-MHC Idd genes control the selection, or alternatively the homing and/or activation of diabetogenic MHC class I restricted T cells.
aim 3 will determine if the Kd and/or Db MHC class I variants contribute to IDDM in NOD mice independently or in combination. This will be tested through outcross analyses of NOD and ALR mice which share all class II, but only some MHC class I alleles.
| Mathews, Clayton E; Graser, Robert T; Bagley, Rebecca J et al. (2003) Genetic analysis of resistance to Type-1 Diabetes in ALR/Lt mice, a NOD-related strain with defenses against autoimmune-mediated diabetogenic stress. Immunogenetics 55:491-6 |
| Serreze, D V; Johnson, E A; Chapman, H D et al. (2001) Autoreactive diabetogenic T-cells in NOD mice can efficiently expand from a greatly reduced precursor pool. Diabetes 50:1992-2000 |
| Mathews, C E; Graser, R T; Serreze, D V et al. (2000) Reevaluation of the major histocompatibility complex genes of the NOD-progenitor CTS/Shi strain. Diabetes 49:131-4 |
