Human vasculitis is a common disease entity. Currently the only known cause of autoimmune vasculitis is immune complex deposition which has been demonstrated in some types of vasculitis but not in others. A lymphocyte-mediated pathogenesis has been suspected but not proven in some vasculitides, especially those occurring in conjunction with collagen-vascular diseases. Nor has a model for an autoimmune cellular vasculitis been developed to the best of our knowledge. We plan to address this gap through the further development of a murine model of autoimmune vasculitis. In this model, lymphocytes are co-cultured with syngeneic endothelium or smooth muscle. After activation, the lymphocytes are injected into syngeneic hosts with a resultant vasculitis seen in various organs. It is hypothesized that either the lympocytes are activated to surface antigens in co-culture and then cross-react with cells in vivo or that the lymphocytes escape normal suppressor regulation by being co-cultured in vitro, or both. The objectives of this project are to further develop this model of autoimmune vasculitis while at the same time addressing some of the pathogenic immune mechanisms which allow the lesions to develop.
The specific aims of this project are to: 1) enhance the number and severity of vasculitis lesions by attenuating suppressor cell systems in culture and in the hosts through the use of cytoxan, irradiation and anti-IJ+ sera; 2) to determine the phenotypes of cells in the lesions as well as the role of immunoglobulin and complement; 3) to investigate the relative contributions to the lessions of injected lymphocytes versus host lymphocytes; 4) to assess the morphologic types of cells in he lesions as well as the vascular damage by electron microscopy; 5) attempt to clone activated, effector T-cells; and 6) to identify the stimulating antigen(s) in the co-culture system.
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