The long-term objective of this project is to develop small molecule inhibitors of MHC class II activity for the treatment of rheumatoid arthritis (RA). The strong genetic association between specific MHC class II alleles, such as HLA-DR molecules containing the shared epitope, and susceptibility to RA provides support to a mechanism in which disease-associated MHC molecules selectively activate CD4 T cells. The hypothesis of this project is that small molecules that block T cell receptor (TCR):HLA-DR-peptide complex formation can prevent autoreactive T cell activation and chronic inflammatory processes in the affect joints. The investigator has developed sensitive screening assays to detect TCR:HLA-DR-peptide interactions and methods to produce sufficient amounts of soluble and functional TCR and HLA-DR-peptide reagents to support analysis of libraries of small molecules. Preliminary studies with another TCR:HLA-peptide pair demonstrate that compounds that specifically inhibit HLA activity in vitro and in vivo can be identified using these screening methods.
The specific aims of the project are to further develop high-throughput screening assays to identify and characterize small molecules that inhibit TCR:HLA-DR-peptide interactions, to examine a large and diverse collection of small molecules for inhibitory activity and to test the immunosuppressive effects of these compounds in T cell-based assays. The results from these studies will provide useful information about TCR:HLA-peptide interactions and could form the basis of a novel class of immunosuppressive drugs to treat human T-cell mediated autoimmune diseases. ? ? ?