IMMUNOMODULATORY STRATEGIES IN AUTOIMMUNE GASTRITIS

许多自身免疫性疾病似乎是由产生促炎细胞因子IFN γ和TNF α的抗原特异性T细胞介导的。 开发一种策略来特异性下调或消除这些自身反应性T细胞而不干扰其他免疫功能将具有重要价值。 这项资助提案的目标是研究两种策略所涉及的机制，这两种策略旨在特异性下调抗原特异性T细胞的活性，并在自身免疫性疾病的小鼠模型中测试这些策略。 先前的研究已经证明，当静脉内注射到幼稚小鼠中时，在TGF β 2存在下用抗原脉冲的抗原呈递细胞（APC）向外周免疫系统传递有效的耐受诱导信号。 越来越多的证据表明，CD 4和CD 8调节性T细胞在该系统中被诱导并介导抗原特异性耐受。 第一个具体目标的目标是了解TGF β处理的APC诱导耐受的机制。 为此，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检查调节性T细胞在该耐受系统中发挥的作用以及它们的一般作用机制。 进一步的研究将涉及调节性T细胞下调效应T细胞功能的精确机制的体外分析。 第二个具体目标的目的是使用自身免疫性胃炎的鼠模型研究TGF β处理的APC的治疗潜力。 BALB/c小鼠新生胸腺切除术（Tx-3）诱导的自身免疫性胃炎明显类似于人类恶性贫血。 T细胞应答在该模型中得到了很好的表征，并且是Th 1型丝氨酸介导的，并且靶向壁细胞的H/K ATP酶的α和β亚基。 该目的旨在确定用ATP酶脉冲的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，并表征与该治疗相关的T细胞应答。 第三个具体目标的目标是探索表达FasL的APC独立地或作为用TGF β处理的APC治疗的补充来治疗自身免疫性疾病的能力。 该目的旨在表征活化的T细胞通过用基因工程化以表达FasL的抗原脉冲APC治疗而在体内靶向消除后的T细胞应答。这种策略可以与TGF β处理的APC结合使用，以成功地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.