IMMUNE MECHANISMS IN PRISTANE INDUCED LUPUS NEPHRITIS

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Intraperitoneal injection of pristane (2,6, 10, 14- tetramethylpentadecane) induces a lupus-like syndrome in nearly all "normal" strains of inbred mice. This syndrome is characterized by disease-specific autoantibody production (anti-Sm, RNP, Su, ribosomal P, double stranded DNA), hypergammaglobulinemia, and severe immune complex-mediated glomerulonephritis closely resembling lupus nephritis. In preliminary studies, it was shown that the disease develops in two phases, each with characteristic types of autoantibodies. cytokines, and renal involvement. Microbial stimulation was found to be an important co-factor in progression to the second. more severe, phase. This project will examine the hypothesis that immune complex deposition is necessary, but not sufficient, for the development of nephritis in pristane-induced lupus. Further, it is hypothesized that a systemic abnormality in macrophage or monocyte phenotype resulting from pristane and/or microbial stimulation leads to the production of proinflammatory cytokines and disease progression. The goal of this project is to define pathways leading to glomerulonephritis in pristane-treated mice and ultimately to relate them to human lupus nephritis. Three specific aims are proposed. The pathology of the renal lesions will be defined in Aim 1. Mesangial and mesangiocapillary lesions will be studied by immunohistochemical techniques to determine whether hypercellularity reflects proliferation of endogenous (mesangial or endothelial) cells vs. influx of exogenous macrophages, lymphocytes or neutrophils. In addition, mesangial matrix deposition will be evaluated, and the time course of the renal changes will be studied. The roles of pro-vs. anti- inflammatory cytokines will be evaluated in Aim 2. Cytokine production in the glomerulus will be compared with that by phagocytes in the peritoneal exudate, spleen and liver to see if systemic abnormalities are present. Expression of cytokine-inducible markers will be studied as a means to evaluate whether the effects of pro-or anti-inflammatory cytokines predominate. The contribution of microbial stimulation to the development of nephritis in pristane-induced lupus will be examined in Aim 3. It is hypothesized that enhanced intestinal permeability resulting from pristane injection increases the translocation of microbial products, such as lipopolysaccharide, into the bloodstream. This may cause systemic activation of monocytes and macrophages, which then are recruited to the glomerulus in response to immune complex deposition, causing progression instead of resolution of the renal lesion. In view of the widespread susceptibility among "normal" mice to pristane-induced lupus, it seems likely that pristane causes lupus- like disease by its effects on a common, distal, part of a lupus pathway, largely bypassing the genetic abnormalities that predispose to spontaneous forms of the disease. The mechanisms involved in this new inducible model of SLE may, therefore, be common to other forms of lupus, including human SLE. Future studies will address the question of whether renal abnormalities similar to those induced by pristane are involved in the pathogenesis of human lupus nephritis.