MEDIATION OF ANTIBODY-INDUCED GLOMERULAR INJURY

最近，一种不依赖白细胞的补体（C '）介导的 肾小球损伤被定义为被动Heymann肾炎（PHN），大鼠 一种非常类似于人类膜性肾病的模型， 肾病综合征的病因有哪些 虽然进一步的观察表明， 提出了C5 b-9膜攻击复合物（MAC）在此过程中的作用， 其他形式的组织损伤，这还没有得到最终证明。 PHN的变体和最近开发的抗体（Ab）导向的， 离体灌流大鼠肾脏中C '介导的肾小球损伤（IPRK） 将用于进一步研究这种独特的组织损伤形式。 肾脏 将含有植入上皮下空间的抗原的细胞灌注到 用含有C '-固定Ab和各种 C ′ =充满和C ′-缺乏血清的来源。 对肾小球的影响 最多可观察两小时。 在该模型的辅助下， 将使用以下方法来寻找MAC功能作用的明确证据 缺乏C6和C8的血清。 其他研究将审查： 中间系统的可能作用; C '-介导的改变， 肾小球筛分特性、GBM电荷残基和肾小球足细胞 形态学;以及通过免疫组织学和 超微结构技术 小组委员会的角色亦将于 通过用特异性抗血清耗尽大鼠的C8体内。 类似 在IPRK和体内的观察也将用抗肾小球药物进行。 基底膜（GBM）抗体。 还将在IPRK中审查的是： 免疫病理事件，局部衍生的血管活性激素和 PHN中肾血流动力学紊乱;和B）血液动力学的影响 影响Ab与肾小球抗原结合的因素。 一个 红细胞灌注的IPRK，其中血流动力学变量接近 生理值，将用于这些研究。 此外，肾小球抗原密度与肾小球疾病的关系 以及它们各自的抗体固定C'和诱导 将探索肾小球损伤。 绵羊抗层粘连蛋白和大鼠GBM抗血清 和定量的体内和体外肾小球结合技术， 用于此目的。 拟议的研究将促进研究者的长期目标， 综合分析影响Ab的因素 在肾小球中的沉积以及这些Ab与C'和 其他介体诱导肾小球损伤。

Recently, a leukocyte-independent form of complement (C')-mediated glomerular injury was defined in passive Heymann nephritis (PHN), a rat model that closely resembles human membranous nephropathy which is a common cause of nephrotic syndrome in adults. While further observations have suggested a role for the C5b-9 membrane attack complex (MAC) in this and other forms of tissue injury, this has not been conclusively shown. Variants of PHN and a recently developed model of antibody (Ab)-directed, C'-mediated glomerular injury in the isolated perfused rat kidney (IPRK) will be used to further study this unique form of tissue injury. Kidneys that contain an antigen planted in the subepithelial space are perfused in vitro with a cell-free perfusate containing C'-fixing Ab and various sources of C'=replete and C'-deficient sera. The effects on glomerular function are oserved for up to two hours. With the aid of this model, definitive evidence of a functional role for the MAC will be sought using sera deficient in C6 and C8. Additional studies will examine: the possible role of intermediary systems; C'-mediated alterations in glomerular sieving properties, GBM charge residues, and glomerular podocyte morphology; and localization of the MAC by immunohistological and ultrastructural techniques. The role of the MAC will also be examined in vivo by depleting rats of C8 with a specific antiserum. Similar observations in the IPRK and in vivo will also be made with antiglomerular basement membrane (GBM) antibody. Also to be examined in the IPRK are: a) a potential relationship between immunopathogenetic events, locally-derived vasoactive hormones and disordered renal hemodynamics in PHN; and b) the influence of hemodynamic factors on the binding of Abs to glomerular antigens. An erythrocyte-perfused IPRK, in which hemodynamic variables approach physiological values, will be used for these studies. In addition, the relationship between the density of glomerular antigens and the abilities of their respective antibodies to fix C' and induce glomerular injury will be explored. Sheep antisera to laminin and rat GBM and quantitative in vivo and in vitro glomerular binding techniques will be used for this purpose. The proposed studies will further the long term goals of Investigator, which are to comprehensively analyze the factors that influence Ab deposition in glomeruli and the ways in which such Abs interact with C' and other mediators to induce glomerular injury.