The aims of the proposed studies - which continue a trend of research that we have contributed to - fall into broad but interrelated categories relevant to the pathogenesis of glomerulonephritis (GN) and graft rejection.
The aims are to: 1. Study the role of T and B cell co- stimulatory signals and adhesion molecules in GN and, 2. Extend knowledge of antibody endothelial cell surface antigen interactions. The first part of the proposal is based on initial evidence that T and B cell constimulatory molecules and adhesion molecules exert a critical role in GN. By using CD40-Ig, CTLA-4-Ig, CD5-Ig, CD2-Ig, LFA-3-Ig, L selectin- Ig, ICAM-1-Ig and VCAM-1-Ig fusion proteins we will determine the role of these molecules in rat anti-GBM crescentic GN and hemorrhagic pneumonitis, and in spontaneous mouse lupus-like GN, and we will try to prevent and to reverse the course of these diseases. In cultured rat mesangial cells and in rat anti-Thy-1 mesangioproliferative GN we will study the role of CD44 - a prominent regulator of leukocyte-extracellular matrix interaction - in the development of glomerulosclerosis. The second part of the proposal is based on evidence we have obtained, that 'in vivo' the interaction of antibodies with cell surface antigens can lead to alteration of the cell surface, including loss of antigens (antigenic modulation) and resistance (adaptation) to the injurious effects of antibodies and complement. Using mice, rats and guinea pigs and protocols designed to prevent or to induce adaptation, we will investigate the consequences of exposure of endothelial cells to monoreactive and polyreactive antibodies. The experimental models available or developed in our laboratory provide the tools for this proposal, using clinical, morphological, immuno- histological, functional, serological and quantitative methods. The ultimate goal is to advance our knowledge of the pathogenesis of GN and xenograft rejection, and test new therapeutic strategics in animal models of human diseases.
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