PATHOGENIC ROLE OF THE COMPLEMENT SYSTEM IN MURINE LUPUS

描述(逐字摘自调查人员摘要)：激活 补体系统由免疫复合体(IC)引起炎症反应。 这是通过补体蛋白的直接作用以及 间接地通过刺激其他中介系统。此外， 补体是对幼稚的最佳体液免疫反应所必需的 抗原与循环ICs的有效处置。这方面的研究 《应用》将考察补语系统在原型中的作用 IC病，系统性红斑狼疮(SLE)。这里，NZBNV F，小鼠模型 将对系统性红斑狼疮进行研究。这些动物的病理特征类似于 人类系统性红斑狼疮，包括发展广泛的 自身抗体和弥漫性增殖性肾小球肾炎 致命的。补体的作用将通过它的抑制来剖析。 由于C3和C5在补体作用中起着关键作用， 在这些研究中，将对抑制每一种药物进行比较。对C3的抑制将是 通过小鼠蛋白CRY(补体受体相关蛋白Y)实现。 将使用两种不同的CRRY给药策略：1)重组 将给予含有非补体激活IgG1“尾”(Crry-Ig)的CRY 对动物来说是慢性的；以及，2)转基因小鼠 内源可溶性Crry的研究(Crry-TG)。C5将被一种 抗小鼠C5单抗，阻断C5的切割和激活 C5。作为一种平行的方法，C3在实验性系统性红斑狼疮中的作用也将是 通过基因打靶(C3-/-)使C3基因缺陷的小鼠确定 老鼠)。这样的研究将确定绝对C3缺乏对人体健康的影响 实验性系统性红斑狼疮。这些研究将仔细评估补体 系统参与实验性系统性红斑狼疮的发病机制。以下是 变量将被衡量：1)临床结果，包括死亡率和 肾功能改变；2)肾脏病理改变，包括 肾小球和肾小管间质进行性纤维化； 促炎症细胞因子在这些模型中上调；4)数量和 循环和肾小球结合的自身抗体的抗原特异性； 5)B淋巴细胞自身免疫激活的相对状态。解剖学研究 补体系统在实验性系统性红斑狼疮中的促炎和抗炎作用 将为人类SLE的疾病机制提供重要的见解，如 在其他IC疾病中也是如此，并可能导致可行的治疗方法 可以在实践中得到应用。

DESCRIPTION (Verbatim from Investigator's Abstract): Activation of the complement system by immune complexes (IC) leads to an inflammatory response. This occurs through the direct actions of complement proteins as well as indirectly via the stimulation of other mediator\systems. Furthermore, complement is necessary for an optimal humoral immune response to naive antigens and effective disposal of circulating ICs. The studies in this application will examine the role of the complement system in the prototypical IC disease, systemic lupus erythematosus (SLE). Here, the NZBNV F, murine model of SLE will be studied. These animals have pathological features similar to those of human SLE, including the development of a wide spectrum of auto-antibodies and diffuse proliferative glomerulonephritis that ultimately is fatal. The roles of complement will be dissected through its inhibition. Because C3 and C5 play pivotal roles in complement actions, the effects of inhibiting each will be compared in these studies. Inhibition of C3 will be achieved with the murine protein Crry (Complement receptor related protein y). Two different strategies of Crry administration will be used: 1) recombinant Crry containing a non-complement activating IgG1 "tail" (Crry-Ig) will be given chronically to animals; and, 2) transgenic mice constitutively producing endogenous soluble Crry will be studied (Crry-tg). C5 will be inhibited with an anti-mouse C5 monoclonal antibody that blocks the cleavage and activation of C5. As a parallel approach, the role of C3 in experimental SLE will also be determined by using mice made deficient in C3 through gene targeting (C3 -/- mice). Such studies will determine the effects of absolute C3 deficiency in experimental SLE. These studies will carefully evaluate how the complement system is involved in the pathogenesis of experimental SLE. The following variables will be measured: 1 ) clinical outcomes, including mortality and renal functional changes; 2) pathological alterations in kidney, including the progressive fibrogenesis occurring in glomeruli and the tubulointerstitium; 3) proinflammatory cytokines that are up regulated in these models; 4) amount and antigen specificity's of circulating and glomerular bound auto-antibodies; and, 5) the relative state of autoimmune activation of B lymphocytes. Dissecting the pro- and anti-inflammatory actions of the complement system in experimental SLE will provide important insights into the mechanisms of disease in human SLE, as well as in other IC diseases and may lead to viable therapeutic approaches that can be applied in practice.