MEDIATION OF ANTIBODY-INDUCED GLOMERULAR INJURY

最近，一种非白细胞形式的补体(C‘)介导的 被动型Heymann肾炎(PHN)大鼠肾小球损伤的定义 与常见的人类膜性肾病非常相似的模型 成人肾病综合征的病因。虽然进一步的观察表明 建议C5b-9膜攻击复合体(MAC)在这一过程中发挥作用 其他形式的组织损伤，这一点尚未得到确凿的证明。 PHN的变体和最近开发的抗体(Ab)导向的模型， C‘介导的大鼠肾脏离体灌流性肾小球损伤 将被用于进一步研究这种独特的组织损伤形式。肾脏 含有种植在上皮下间隙中的抗原的细胞被灌流到 无细胞灌流液中含有C‘-固定抗体和各种 C‘=全血和C’缺乏血清的来源。对肾小球的影响 功能最长可保存两个小时。借助于这个模型， 将使用以下方法寻找互委会职能作用的确凿证据 缺乏C6和C8的血清。其他研究将审查： 中介系统的可能作用；C‘介导的改变 肾小球筛选特性、肾小球基底膜电荷残留量和肾小球足细胞 通过免疫组织学和免疫组织化学方法对MAC进行定位 超微结构技术。互委会的角色也将在 用一种特定的抗血清耗尽大鼠的C8。类似 在IPRK和体内的观察也将通过抗肾小球进行。 基底膜抗体。 将在IPRK中审查的还有：a)潜在的 免疫致病事件、局部衍生的血管活性激素和 PHN患者肾脏血流动力学紊乱；b)血流动力学的影响 影响抗体与肾小球抗原结合的因素。一个 红细胞灌注型IPRK，血流动力学变量接近 生理价值，将用于这些研究。 此外，肾小球抗原密度与肾小球密度的关系 以及它们各自的抗体固定C‘并诱导 本课程将探讨肾小球损伤。羊抗层粘连蛋白和大鼠GBM的抗血清 而定量的体内和体外肾小球结合技术将是 用于此目的。 拟议的研究将促进调查员的长期目标， 其中综合分析了影响抗体的因素 肾小球内的沉积及其与C‘和C’的相互作用 其他诱导肾小球损伤的介质。

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.