IMMUNOMODULATORY STRATEGIES IN AUTOIMMUNE GASTRITIS

许多自身免疫性疾病似乎是由抗原特异性T细胞介导的，这些细胞产生促炎细胞因子，ifnγ和TNFalpha。开发一种策略，在不干扰其他免疫功能的情况下特异性下调或消除这些自身反应性T细胞，将具有很大的价值。这项拨款提案的目标是研究两种策略所涉及的机制，这些策略旨在特异性下调抗原特异性T细胞的活性，并在具有良好特征的自身免疫性疾病小鼠模型中测试这些策略。先前的研究表明，将抗原呈递细胞（APCs）在TGFbeta2存在下脉冲，通过静脉注射到幼年小鼠体内，向外周免疫系统传递一个有效的耐受诱导信号。越来越多的证据表明，CD4和CD8调节性T细胞在该系统中被诱导和介导抗原特异性耐受。第一个具体目标是了解tgf - β处理的APCs诱导耐受性的机制。为了达到这个目的，调节性T细胞在这个耐受系统中所起的作用以及它们的一般作用机制将在使用敲除小鼠、中和抗体和TCR转基因T细胞转移系统的体内研究中进行检验。进一步的研究将包括对调节性T细胞下调效应T细胞功能的精确机制的体外分析。第二个具体目标是利用小鼠自身免疫性胃炎模型研究tgf β治疗APCs的治疗潜力。BALB/c小鼠的新生儿胸腺切除术（Tx-3）诱导自身免疫性胃炎，明显类似于人类恶性贫血。在这个模型中，Tile T细胞的反应已经被很好地表征，并且是th1型细胞因子介导的，针对壁细胞H/K atp酶的α和β亚基。该目的旨在确定用atp酶脉冲tgf - β处理的apc治疗Tx-3小鼠是否可以“治愈”或改善自身免疫性胃炎，并表征与这种治疗相关的T细胞反应。第三个具体目标是探索fasl表达的apc独立治疗自身免疫性疾病的能力，或作为tgf - β治疗apc的补充。这一目的旨在描述激活的T细胞在体内通过抗原脉冲apc基因工程表达FasL被靶向消除后的T细胞反应。该策略可与tgf - β治疗的apc联合使用，成功治疗已建立的自身免疫性疾病。

Many autoimmune diseases appear to be mediated by antigen-specific T cells that produce the pro-inflammatory cytokines, IFNgamma and TNFalpha. It would be of great value to develop a strategy to specifically downregulate or eliminate these autoreactive T cells without interfering with other immune functions. The goal of this grant proposal is to study the mechanisms that are involved in two strategies designed to specifically downregulate the activity of antigen-specific T cells and to test these strategies in a well-characterized murine model of autoimmune disease. Previous studies have demonstrated that antigen presenting cells (APCs) pulsed with antigen in the presence of TGFbeta2 transmit a potent tolerance-inducing signal to the peripheral immune system when injected intravenously into naive mice. Accumulating evidence suggests that CD4 and CD8 regulatory T cells are induced and mediate antigen-specific tolerance in this system. The goal of the first specific aim is to understand the mechanisms involved in tolerance induced by TGFbeta-treated APCs. In this aim, the role that regulatory T cells play in this system of tolerance as well as their general mechanism(s) of action will be examined in in vivo studies using knock-out mice, neutralizing antibodies and a TCR transgenic T cell transfer system. Further studies will involve in vitro analyses of the precise mechanisms utilized by regulatory T cells to downregulate effector T cell function. The goal of the second specific aim is to investigate the therapeutic potential of TGFbeta-treated APCs using a murine model of autoimmune gastritis. Neonatal thymectomy (Tx-3) in BALB/c mice induces an autoimmune gastritis that markedly resembles human pernicious anemia. Tile T cell response has been well characterized in this model and is Th1-type cytokine-mediated and targeted to the alpha and beta subunits of H/K ATPase of parietal cells. This aim is designed to determine whether treatment of Tx-3 mice with ATPase-pulsed TGFbeta-treated APCs can "cure" or ameliorate autoimmune gastritis and to characterize the T cell response that is associated with this treatment. The goal of the third specific aim is to explore the ability of FasL-expressing APCs to treat autoimmune disease either independently or as a supplement to treatment with TGFbeta-treated APCs. This aim is designed to characterize the T cell response after activated T cells have been targeted for elimination in vivo by treatment with antigen-pulsed APCs genetically engineered to express FasL. This strategy may be used in conjunction with TGFbeta-treated APCs to successfully treat established autoimmune disease.