In Vivo Studies of ANCA Glomerulonephritis Pathogenesis

将研究人ANCA肾炎的小鼠模型，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。该模型包括将抗MPO抗体或抗MPO淋巴细胞(来自用小鼠MPO免疫的MPO-/-小鼠)转移到MPO正常产生的受体小鼠中。特定目的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，并且疾病的诱发受到增强或减弱中性粒细胞活性的因素的影响。特异靶2将验证抗MPO肾小球肾炎可由特定正义和反义肽诱导的假说，并涉及逃避调节机制。中性粒细胞的作用将通过评估 中性粒细胞的耗尽、中性粒细胞功能的增强、中性粒细胞功能的阻断以及缺乏重要中性粒细胞效应功能的基因敲除小鼠的使用。通过比较不同比例的抗MPO T细胞和B细胞对疾病的诱导作用，评估抗MPO T细胞和抗MPO免疫球蛋白的相对致病重要性。用不同的重组正义和互补的小鼠MPO多肽为模型制备抗MPO抗体，研究不同MPO表位的相对免疫原性和致病性。调节性淋巴细胞在下调抗MPO自身免疫中的作用将通过将免疫活性小鼠中抑制抗鼠MPO活性的不同淋巴细胞亚群转移到免疫缺陷RAG2-/-来研究 采用抗MPO免疫反应的小鼠评估抗MPO的抑制情况 自身免疫反应。这项拟议的研究将加深我们对ANCA肾炎发病机制的理解，并应指出这种侵袭性疾病的改进治疗策略，这一点非常重要，因为目前ANCA肾炎的治疗并不完全有效，而且是有毒的。

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.