T CELL TOLERANCE INDUCED BY FAS LIGAND EXPRESSING APCS

描述（来自应用程序）： 本提案阐述了RFA AR-97-001的目标：治疗设计 通过影响抗原加工来防止对自身的异常反应。 的 设计预防自身免疫性疾病的策略的挑战是， 操纵免疫应答，使得自身免疫应答 在不中断正常免疫反应的情况下特异性地减少，或 诱发代偿机制，这可能会绕过治疗 并导致不良副作用。 在大多数情况下，这必须是 在不清楚负责的抗原的情况下完成 的发病机制。 本提案的总体目标是制定一个 治疗策略，其中修饰的抗原呈递细胞 使得它们表达Fas配体，用于消除自身反应性T 细胞具体 将此策略用于 预防和治疗自身免疫性疾病将在三个测试 人类自身免疫性疾病的动物模型-gld小鼠模型 淋巴增生性疾病;刘易斯大鼠实验性变态反应 器官特异性自身免疫性疾病和多个器官特异性自身免疫性疾病的脑炎（EAE）模型 硬化症（MS）;和全身性自身免疫性疾病的NZB/NZW F1小鼠模型 疾病和人系统性红斑狼疮（SLE）。 中央 假设抗原特异性T细胞耐受可由APC诱导 自身反应性T细胞可以特异性地 通过表达呈递自身抗原的同基因Fas配体的APC消除 to the T细胞. 这一假设得到了最近研究结果的有力支持 这表明表达Fas配体APC可以诱导同种异体T细胞 耐受性，并且这种T细胞耐受性的诱导由 耗尽抗原特异性T细胞。 一种独特的重组腺病毒 系统，该系统已被开发用于表达高水平的Fas 原代培养细胞中的Fas配体，将用于操纵Fas配体 在各种APC中表达。 Fas配体表达的治疗作用 APC将在三种不同的系统中使用Fas配体进行评估 用于治疗Fas的同源巨噬细胞上的表达 配体缺陷型gld/gld小鼠;表达Fas配体的同基因胶质细胞 和用于治疗刘易斯大鼠中的EAE的呈递MBP自身抗原;和Fas 配体同源巨噬细胞用于治疗NZB/W小鼠。 治疗 将在自身免疫表现之前或之后开始， 将评估自身免疫的免疫学和临床参数， 时间 这种新方法将基因治疗与细胞治疗相结合， 靶向自身反应性T细胞。 这项研究的完成将奠定 治疗方法的基础，可以预防，延迟或逆转 人类自身免疫性疾病的慢性、衰弱和危及生命的症状 疾病，包括MS和SLE。

DESCRIPTION (from the application): This proposal addresses the objective of RFA AR-97-001: Design of therapies to prevent abnormal response to self by affecting antigen processing. The challenge in designing strategies for prevention of autoimmune disease is to manipulate the immune response such that the autoimmune response is curtailed specifically without interruption of the normal immune response or elicitation of compensatory mechanisms, which could bypass the therapeutic strategy and result in adverse side-effects. In most cases, this must be accomplished in the absence of clear knowledge of the antigen(s) responsible for the pathogenesis. The overall goal of this proposal is to develop a therapeutic strategy in which antigen presenting cells, which are modified such that they express Fas ligand, are used to eliminate autoreactive T cells specifically. The feasibility of using this strategy for the prevention and treatment of autoimmune disease will be tested in three animal models of human autoimmune disease - the gld mouse model of lymphoproliterative disease; the Lewis rat experimental allergic encephalitis (EAE) model of organ-specific autoimmune disease and multiple sclerosis (MS); and the NZB/NZW F1 mouse model of systemic autoimmune disease and human systemic lupus erythematosus (SLE). The central hypothesis is that antigens-specific T cell tolerance can be induced by APCs that express Fas ligand, and that autoreactive T cells can be specifically eliminated by syngeneic Fas ligand expressing APCs that present autoantigen to the T cells. This hypothesis is strongly supported by recent findings that indicate that APCs that express Fas ligand can induce allogeneic T-cell tolerance and that induction of this T-cell tolerance is mediated by depletion of antigens-specific T cells. A unique recombinant adenovirus system, which has been developed for the expression of high levels of Fas ligand in primary culture cells, will be used to manipulate Fas ligand expression in various APCs. The therapeutic effect of Fas ligand expressing APCs will be evaluated in three different systems using Fas ligand expression on syngeneic macrophages for the treatment of Fas ligand-deficient gld/gld mice; syngeneic glial cells that express Fas ligand and present MBP autoantigen for the treatment of EAE in Lewis rats; and Fas ligand syngeneic macrophages for the treatment of NZB/W mice. Treatment will be initiated prior to or after manifestation of autoimmunity and immunologic and clinical parameters of autoimmunity will be assessed over time. This novel approach combines gene therapy with cellular therapy to target autoreactive T cells. Accomplishment of this study will lay the basis for a therapeutic approach that may prevent, delay, or reverse the chronic, debilitating, and life-threatening symptoms of human autoimmune diseases, including MS and SLE.