PROFILING SYNOVIAL VASCULATURE IN ARTHRITIS-PRONE RATS

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DESCRIPTION (provided by applicant): Adjuvant arthritis (AA) is inducible in the Lewis rat (RT.11) by s.c. injection of heat-killed M. tuberculosis H37Ra (Mtb), and it serves as an excellent model for human rheumatoid arthritis (RA). Arthritic Lewis rats raise T cell response to the 65 kD mycobacterial heat-shock protein (Bhsp65), and the region 180-188/177-191 of Bhsp65 is believed to harbor the pathogenic epitope for the Lewis rat. It is believed that in AA, the T cells primed by Bhsp65 (within Mtb) migrate into the synovium of joints and cause tissue damage presumably by recognizing a crossreactive self antigen (that has not yet been fully defined). In this regard, one proposition is that the antigenic targets of Bhsp65- primed T cells might be homologous self heat-shock proteins (Hsp). Considering that Hsp are ubiquitously expressed proteins and that they are highly conserved in nature, it is intriguing to find that immunization of Lewis rats with Mtb primarily leads to induction of arthritis without significant clinical features involving other organs. We propose that the synovial vascular endothelium displays unique molecular markers, including homing molecules that facilitate efficient trafficking of potentially arthritogenic T cells primed by Mtb into the joints of the Lewis rat, and that this attribute could be one of the important determinants of joints as the primary target (organ-specificity) of the Bhsp65- specific T cells in AA. Furthermore, unlike the Lewis rat, the WKY rat [which is of the same MHC haplotype (RT. 11) as the Lewis rat] is resistant to induction of AA. However, Mtb-challenged WKY rats are not deficient in raising potent T cell response to Bhsp65 or its potentially arthritogenic epitope 180-188/177-191. We suggest that the target organ differences between these two rat strains might contribute to their differential susceptibility to AA. Therefore, to fully understand the pathogenic mechanisms of target organ damage in arthritis, it is critical to examine the physiological and functional attributes of the vascular endothelium within the joints. This study is aimed at - (Aim 1) identification of'address molecules' for the synovial vascular endothelium of the target organ (joints) in the to determine whether vascular endothelium of the joints differs significantly from that of other organs, and (Aim 2) comparing the characteristics of synovial vasculature of Lewis and WKY rats. We believe that identification of the synovium vascular-homing markers for the joint would significantly advance our understanding of the pathogenesis of AA and RA, and also provide promising novel targets for the treatment of autoimmune arthritis.