In Vivo Studies of ANCA Glomerulonephritis Pathogenesis

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A mouse model of human ANCA glomerulonephritis will be studied to advance the understanding of the pathogenic processes that cause glomerular injury and the immunogenic events that lead to the autoimmune response. The model involves transfer of anti-MPO antibody or anti-MPO lymphocytes (derived from MPO-/- mice immunized with mouse MPO) into recipient mice with normal MPO production. Specific Aim 1 will test the hypothesis that neutrophils are the primary effector cells of anti-MPO glomerulonephritis, and disease induction is influenced by factors that enhance or diminish neutrophil activity. Specific Aim 2 will test the hypothesis that anti-MPO glomerulonephritis can be induced by specific sense and anti-sense peptides, and involves escape from regulatory mechanisms. The role of neutrophils will be evaluated by assessing the effects of depletion of neutrophils, enhancement of neutrophil function, blockade of neutrophil function, and use of knock out mice lacking important neutrophil effector functions. The relative pathogenic importance of anti-MPO T cells versus anti-MPO IgG will be evaluated by comparison of disease induction by transfer of varying proportions of anti-MPO T cell and B cells. The relative immunogenicity and pathogenicity of different MPO epitopes will be investigated by using different recombinant sense and complementary murine MPO peptides to prepare anti-MPO antibodies for the model. The role for regulatory lymphocytes in the down regulation of anti-MPO autoimmunity will be investigated by transferring different subsets of lymphocytes from immune competent mice that have suppressed anti-mouse MPO activity into immune deficient RAG2-/- mice that have adopted an anti-MPO immune response to asses the suppression of the anti-MPO autoimmune response. The proposed research will refine our understanding of the pathogenesis of ANCA glomerulonephritis and should point to improved therapeutic strategies for this aggressive disease, which is very important because current treatment of ANCA glomerulonephritis is not fully effective and is toxic.