Rheumatoid arthritis (RA) is a common disorder that causes considerable morbidity and excess mortality. Treatment is currently empirical and inadequate. The HLA-DR molecules, which are polymorphic class II glycoproteins encoded by the human major histocompatibility complex (MHC) expressed on the surfaces of antigen presenting cells, play a central role in the human immune response by binding peptide antigens in a manner that can be recognized by thymocytes and T cells. Most of the DR polymorphism within the human population resides in the DRB1 locus, specifically within three hypervariable regions in the exon encoding the beta1 domain. Approximately 90% of individuals with RA can be shown to have inherited one or more alleles at the HLA-DRB1 locus that encode a group of DRbeta chains that share very closely related primary amino acid sequences within the third hypervariable region. This finding suggests that DR molecules possessing RA-associated sequences participate directly in the pathogenesis of RA. It is likely that the understanding of the pathogenesis of RA would be aided considerably if the mechanism by which DR molecules predispose to RA were elucidated. However, it has been difficult to approach this problem experimentally because of the limitations in studying MHC class II function in humans. In this project, lines of transgenic mice and rats will be produced that express either of two different HLA-DR molecules, one that predisposes humans to RA and one that apparently protects humans against RA. Experiments will be done to test whether the transgene products are expressed in a physiologic manner and whether they present antigen to T cells. If so, studies will be carried out of the potential influence of the DR transgenes on two experimental models of arthritis in rats and mice, collagen-induced arthritis and adjuvant arthritis, and the possibility will be examined that the RA-associated DR molecule can specifically present peptides associated with one or both of the experimental arthritides to DR-restricted, peptide-specific T cells. If such a DR-restricted T cell response can be demonstrated, the capacity of the responding T cells to induce disease upon transfer to transgenic recipient animals will be investigated, as will the fine specificity of the responding T cells for peptide and DR molecule. The anticipated result of this project will be the production of transgenic rodent lines that will be exceedingly useful for the study of RA, as well as an improved understanding of the capacity of RA-associated DR molecules to bind and present peptide antigens known to be involved in immune recognition that leads to inflammatory arthritis.
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