T CELL TOLERANCE INDUCED BY FAS LIGAND EXPRESSING APCS

描述(来自应用程序)： 本提案涉及RFA AR-97-001的目标：治疗设计 通过影响抗原的处理来防止对自身的异常反应。这个 设计预防自身免疫性疾病的策略面临的挑战是 操纵免疫反应，使自身免疫反应 特别是在不中断正常免疫反应的情况下被抑制或 引发代偿机制，可以绕过治疗性 策略和结果都有不良副作用。在大多数情况下，这必须是 在没有明确抗原知识的情况下完成(S)负责 对于发病机制的解释。这项提案的总体目标是开发一种 在治疗策略中，抗原提呈细胞被修饰 以便它们表达Fas配体，用于消除自身反应性T 特别是细胞。使用这一策略的可行性 自身免疫性疾病的预防和治疗将在三个月内进行测试 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；Lewis大鼠实验性变态反应 器官特异性自身免疫性疾病脑炎(EAE)模型及多发性 系统性自身免疫的NZB/NZW F1小鼠模型 疾病和人类系统性红斑狼疮(SLE)。中环 假设APC可以诱导抗原特异性T细胞耐受 表达Fas配体，自身反应性T细胞可以特异性地 被表达呈现自身抗原的APC的同基因Fas配体消除 T细胞。最近的研究结果有力地支持了这一假设。 提示表达Fas配体的APC可诱导同种异体T细胞 耐受性和这种T细胞耐受性的诱导是通过 抗原特异性T细胞的耗尽。一种独特的重组腺病毒 该系统是为高水平表达Fas而开发的 原代培养细胞中的配体，将用于操纵Fas配体 在不同的APC中表达。表达Fas配体的临床疗效观察 APC将在三个不同的系统中使用Fas配体进行评估 同基因巨噬细胞在Fas治疗中的表达 配体缺陷的GLD/GLD小鼠；表达Fas配体的同基因胶质细胞 并提出MBP自身抗原用于治疗Lewis大鼠的EAE；以及Fas 配体同基因巨噬细胞治疗NZB/W小鼠的实验研究治疗 将在自身免疫表现之前或之后启动，并且 将对自身免疫的免疫学和临床参数进行评估 时间到了。这一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。这项研究的完成将为 一种治疗方法的基础，这种方法可以预防、延迟或逆转 人类自身免疫的慢性、衰弱和危及生命的症状 疾病，包括多发性硬化和系统性红斑狼疮。

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.