CELL MEDIATED GLOMERULONEPHRITIS IN A NEW MODEL

描述(摘自申请人摘要)：男性肾小球肾炎 是导致患者发病率、死亡率和需要透析的主要原因。 支持和移植。人类肾小球肾炎最常见，如果 并不是所有病例都与自身免疫原因有关。许多间接证据 提示细胞免疫在细胞免疫中起着重要作用。 肾小球肾炎的发生。有被广泛研究的模型 给药致实验性肾小球肾炎 肾脏成分的抗体，随后是抗原沉积 通过抗体在肾脏或循环中沉积来执行免疫 复合体。系统性免疫复合体疾病的其他内源性模型 以旁观者的角色损害肾脏。这些型号不能提供贷款 致力于研究与细胞介导有关的致病事件 免疫在自身免疫性肾小球肾炎发生时的肾脏 它本身就是目标。增殖性实验性自身免疫模型的建立 在近亲交配的哺乳动物中以前没有发生过肾小球肾炎 物种。我们已经使用了一种新的方法来揭露一种致肾炎的 并开发了一种新的实验性自身免疫模型 近交系同基因大鼠肾小球肾炎。此模型允许，对于 首次应用生物工具研究病原学 增生性肾小球肾炎的发生机制 以前可用。本提案的长期目标是 继续他们对细胞介导机制的研究 免疫在肾小球肾炎发病机制中的作用 模型，并进一步阐明细胞免疫的相互作用 而经典抗体在这一过程中介导了损伤。的具体目标 目前的建议是：1)更好地描述发展和 实验性自身免疫性肾小球肾炎的自然病程与时间 剂量临床病理研究；2)检测抗体在疾病中的作用 开发和评估抗体单独和联合的独立作用 利用被动转移抗体产生疾病的细胞和 杂交瘤；3)检测细胞免疫在细胞免疫中的作用 通过过继转移研究的发病机制，诱导B细胞缺陷 用抗原特异性T细胞克隆进行研究；4)鉴定 致肾肽(S)负责诱导实验性肾小球疾病 自身免疫性肾小球肾炎，将这些多肽分成最低限度 免疫原性片段，并确定其氨基酸序列，然后 产生多肽和类似物并对其进行生产和预防检测 疾病的威胁。 间接证据有力地表明，引起病毒的抗原 实验性自身免疫性肾小球肾炎的动物模型是 与导致人类古德帕斯综合症的抗原相同。这种哺乳动物 模型提供了一种独特的格式来检查自身免疫中的致病事件 肾小球肾炎以前没有，因为缺乏 合适的动物模型。从该模型派生的信息可能是 直接适用于人类疾病的对应物--好牧场 综合征，可能还有其他类型的肾小球肾炎。

DESCRIPTION (Adapted from Applicant's Abstract): Glomerulonephritis in man is a major cause of patient morbidity, mortality, and need for dialysis support and transplantation. Human glomerulonephritis appears in most, if not all, cases to be related to autoimmune causes. Much indirect evidence suggests that cell mediated immunity plays an important role in the development of glomerulonephritis. There are extensively studied models of experimental glomerulonephritis induced by administration of performed antibodies to constituents of the kidney, deposition of antigens followed by antibody in the kidney, or deposition of circulating performed immune complexes. Other endogenous models of systemic immune complex disease damage the kidney in its by stander role. These models do not lend themselves to the study of pathogenetic events involved with cell mediated immunity in the production of autoimmune glomerulonephritis when the kidney itself is the target. A model of proliferative experimental autoimmune glomerulonephritis has not previously been developed in an inbred mammalian species. We have utilized a novel approach to expose a nephritogenic antigen and have developed a new model of experimental autoimmune glomerulonephritis in inbred syngeneic rats. This model allows, for the first time, application of biologic tools to investigate pathogenetic mechanisms in the production of proliferative glomerulonephritis not previously available. The long term objectives of the present proposal are to continue their investigations into the mechanisms by which cell mediated immunity contributes to the pathogenesis of glomerulonephritis in this new model and to further delineate the interaction of cell mediated immunity and classic antibody mediated damage in this process. The specific aims of the present proposal are: 1) to better characterize the development and natural course of this experimental autoimmune glomerulonephritis with time dose clinicopathologic studies; 2) to examine the role of antibody in development and assess the independent role of antibody alone and with cells in production of disease using passively transferred antibody and hybridomas; 3) to examine the role of cell mediated immunity in pathogenesis by adoptive transfer studies, induction in B cell deficient rats, and studies with antigen specific T cell clones; 4) to identify nephitogenic peptide(s) responsible for induction of experimental autoimmune glomerulonephritis, fractionate these peptide into minimal immunogenic fragments, and determine their amino acid sequence, then generate peptide and analog and examine them for production and prevention of disease. Indirect evidence strongly suggests that the antigen which causes experimental autoimmune glomerulonephritis in their animal model is the same antigen that causes Goodpastures syndrome in man. This mammalian model provides a unique format to examine pathogenetic events in autoimmune glomerulonephritis not previously available because of lack of an appropriate animal model. Information derived from this model may be directly applicable to the human disease counter part, Goodpastures syndrome, and possibly other types of glomerulonephritis.