EXPERIMENTAL STUDIES ON IMMUNE GLOMERULONEPHRITIS

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The investigations concern the cellular interactions between intrinsic glomerular cells and infiltrating immune cells in immunologically mediated glomerular injury. Glomerular disease models to be examined include glomerulonephritis mediated by antisera to glomerular basement membrane and by deposition of immune complexes. The basic experimental approach consists of enzymatic disassociation of injured glomeruli into a suspension of constituent cells (both endogenous and exogenously derived), isolation of particular cell types, and the assay of their cellular activities in short-term and long-term tissue culture. Particular emphasis will be on the contributions of the resident ad infiltrating mononuclear phagocytes. Intraglomerular macrophages will be assayed for specifically immune functions such as antigen presentation, secretion or display of Interleukin-1, and secretion of lymphocyte chemoattractants and arachidonic acid metabolites. Cultures of endogenous glomerular cells are to be assayed for their capacity to regulate monocyte recruitment to the glomerulus. Mesangial cells and epithelial cells will be further evaluated for their ability to modulate the immunoreactivity of macrophages. The first parameter to be examined will be the expression of Ia antigens by intraglomerular and peritoneal macrophages in the presence of factors secreted by intrinsic glomerular cells. In parallel studies, intraglomerular and interstitial lymphocytes will be obtained from immune renal lesions involving pre-sensitization of rats to particular antigens and the subsequent placing of that antigen in the glomerulus. The lymphocytes will be phenotypically classified by mononuclear antibodies. They will be evaluated for their state of activation, as determined by antigen-driven proliferation and their release of the immunoregulatory lymphokines: Interleukin-2, gamma interferon, and monocyte chemotaxis factors. Finally, the effect of humoral and cellular immune stimuli on intrinsic glomerular cell function will be examined, with the mesangial cell expression of angiotensin II receptors as the model system to be assayed.