Susceptibility to autoimmune diseases has been directly linked to the major histocompatibility complex (MHC); however, the role the MHC gene products play has not been ascertained. We propose to utilize a recently described murine model of rheumatoid arthritis (RA) to investigate the relationships between self-peptide recognition, alloreactivity, and autoimmunity. The basis for this model is the alloreactivity of a T cell, R28, specific for the RNase (41-61)/I-Ak determinant to the I-Ag7 molecule. R28 TCR transgenic mice (KRN) when crossed to the NOD strain exhibited pronounced joint inflammation. The KRN x NOD mice share most of the major clinical, histological and immunological features of human rheumatoid arthritis. The 100% disease incidence and the early and reproducible time of onset make this a very attractive and powerful model. In the studies proposed in aim I, we will identify using peptide libraries an allomimotope peptide, which can stimulate the KRN T cells. This recognition will then be compared and contrasted to that of RNase (41-61)/I-Ak. These studies will provide a structural definition of the different ligands recognized by KRN T cells and insights into what type of recognition events are involved in autoreactivity.
In aim II we propose to test in vivo the ability of altered peptide ligands to block the induction and development of RA. We will also involve directly visualizing in vivo the location and function of the autoreactive T cells. These in vivo studies will establish the potential of altered peptide ligands to treat RA.
In aim III, we propose to identify what properties of the target ligands are necessary for disease induction. These studies will involve a second alloligand of the KRN T cells, I-AkA65, which differs from the I-Ag7 molecule in several biochemical and functional properties. Overall, these proposed studies will provide important new insights into the relationship between the T cell recognition of antigen and the development of autoimmune disease.
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