PATHOGENIC ROLE OF THE COMPLEMENT SYSTEM IN MURINE LUPUS

补体系统在鼠狼疮中的致病作用

• 批准号: 6921653
• 负责人: RICHARD J. QUIGG
• 金额: $ 3.21万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921653
• 关键词: B lymphocyte; animal mortality; antigen antibody reaction; autoantibody; chemical cleavage; complement; complement inhibitors; complement pathway; complement receptor; cytokine; disease /disorder model; fibrogenesis; gene targeting; genetically modified animals; immunoglobulin G; inflammation; kidney function; laboratory mouse; monoclonal antibody; pathologic process; recombinant proteins; systemic lupus erythematosus

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.

描述（逐字研究来自研究者的摘要）：激活 免疫复合物（IC）的补体系统导致炎症反应。 这是通过补体蛋白质的直接作用以及 通过刺激其他调解人\系统间接。此外， 补体对于对天真的最佳体液免疫反应是必需的 抗原和有效处理循环IC。关于这一点的研究 应用将检查补体系统在原型中的作用 IC疾病，全身性红斑狼疮（SLE）。在这里，NZBNV F，鼠模型 SLE将研究。这些动物具有类似的病理特征 人类SLE的那些，包括开发广泛的 自身抗体和弥漫性增殖性肾小球炎，最终是 致命的。补体的作用将通过其抑制作用进行解剖。 因为C3和C5在补充动作中扮演关键角色，所以 在这些研究中将比较抑制每一个。 C3的抑制作用将是 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管理策略：1）重组 将给出包含不配合激活IgG1“尾巴”（crry-ig）的crry 长期向动物;以及，2）转基因小鼠组成性产生 将研究内源性可溶性皱纹（Crry-TG）。 C5将被抑制 抗小鼠C5单克隆抗体，阻塞了裂解和激活 C5。作为一种平行的方法，C3在实验SLE中的作用也将是 通过使用小鼠通过基因靶向在C3中的缺陷确定（C3 - / - 小鼠）。这样的研究将确定绝对C3缺乏的影响 实验性SLE。这些研究将仔细评估如何补充 系统参与实验SLE的发病机理。下列 将测量变量：1）临床结果，包括死亡率和 肾功能变化； 2）肾脏的病理改变，包括 在肾小球和肾小管间质中发生的进行性纤维化； 3） 在这些模型中受到调节的促炎细胞因子； 4）金额和 循环和肾小球结合自身抗体的抗原特异性；和， 5）B淋巴细胞自身免疫激活的相对状态。解剖 实验SLE中补体系统的促和抗炎作用 将提供对人SLE疾病机制的重要见解，因为 以及其他IC疾病，可能导致可行的治疗方法 可以在实践中应用。