In Vivo Studies of ANCA Glomerulonephritis Pathogenesis

将研究人类ANCA肾小球肾炎小鼠模型，以促进对导致肾小球损伤的致病过程和导致自身免疫反应的免疫原性事件的理解。该模型通过将抗MPO抗体或抗MPO淋巴细胞（来源于用小鼠MPO免疫的MPO-/-小鼠）转移到产生正常MPO的受体小鼠中。特异性目的1将验证中性粒细胞是抗mpo肾小球肾炎的主要效应细胞的假设，并且疾病诱导受中性粒细胞活性增强或减弱的因素的影响。特异性目的2将验证抗mpo肾小球肾炎可由特异义肽和反义肽诱导，并涉及逃避调节机制的假设。中性粒细胞的作用将通过评估

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.