PATHOGENIC ROLE OF THE COMPLEMENT SYSTEM IN MURINE LUPUS

描述（逐字摘自研究者摘要）： 免疫复合物（IC）引起的补体系统的炎症反应。 这是通过补体蛋白的直接作用以及 间接地通过刺激其他介质\系统。此外，委员会认为， 补体是最佳的体液免疫应答所必需的， 抗原和循环IC的有效处置。这方面的研究 应用程序将检查补体系统在原型中的作用 IC疾病，系统性红斑狼疮（SLE）。在此，NZBNV F小鼠模型 将研究SLE。这些动物的病理特征类似于 这些人类SLE，包括发展广泛的 自身抗体和弥漫性增生性肾小球肾炎， 致命的补体的作用将通过其抑制作用来剖析。 由于C3和C5在补体作用中起关键作用， 将在这些研究中比较抑制每一种的效果。C3的抑制将是 用鼠蛋白Crry（补体受体相关蛋白y）实现。 将使用两种不同的Crry施用策略： 将给予含有非补体激活IgG 1“尾”的Crry（Crry-Ig） 慢性动物;和，2）转基因小鼠组成型生产 将研究内源性可溶性Crry（Crry-tg）。C5将被抑制， 抗小鼠C5单克隆抗体，其阻断 C5.作为一种平行的方法，C3在实验性SLE中的作用也将被研究。 通过使用通过基因靶向（C3 -/-）使C3缺陷的小鼠来测定 小鼠）。这些研究将确定绝对C3缺乏对 实验性SLE这些研究将仔细评估如何补充 系统参与了实验性SLE的发病机制。以下 将测量变量：1）临床结局，包括死亡率和 肾功能改变; 2）肾脏病理改变，包括 肾小球和肾小管中发生进行性纤维化; 3） 在这些模型中上调的促炎细胞因子; 4）量和 循环和肾小球结合自身抗体的抗原特异性;以及， 5)自身免疫激活B淋巴细胞的相对状态。解剖 补体系统在实验性SLE中的促炎和抗炎作用 将为人类SLE疾病机制提供重要见解， 以及其他IC疾病，并可能导致可行的治疗方法， 可以在实践中应用。

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.