Mechanism of Glomerular Injury Mediated by CD8^+ Lymphocytes in Anti-GBM Nephritis of WKY Rats

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We developed a new model of anti-glomerular basement membrane glomerulonephritis in WKY rats. The model was characterized with glomerular infiltration of CD8^+ lymphocytes and macrophages and crescent formation. Since the glomerulonephritis was suppressed in WKY rats which were treated with anti-CD8 antibody to deplete CD8^+ lymphocytes, it was presumed that the CD8^+ lymphocytes playd a central role in the induction of the glomerulonephritis. Namely the CD8^+ lymphocytes relate to the glomerular accumulation of macrophages, glomerular injury, and crescent formation in a direct or indirect manner. Therefore, this is a novel model in which lymphocytes regulate induction of glomerulonephritis.In the present study, we examined an involvement of adhesion molecules, cytokines, and factors to injure glomerular structure. We found an increase of ICAM-1 expression in the glomerular endothelial cells at both protein and mRNA levels after injection with anti-glomerular basement membrane antibody. The increase of ICAM-1 expression correlated well with the accumulation of CD8^+ lymphocytes and macrophages and blocking of ICAM-1-LFA-1 interaction by administration of monoclonal antibodies against thesemolecules suppressed the glomerulonephritis induction. Through search for cytokines which might induce enhancement of ICAM-1 expression, we found that TNF-alpha expression in the glomeruli well-related with the glomerular ICAM-1 expression, suggesting a role of TNF-alpha. A participation of MCP-1 and perforin was suggested for the glomerular accumulation of macrophages and glomerular injury in this model.