IMMUNOMODULATORY STRATEGIES IN AUTOIMMUNE GASTRITIS

自身免疫性胃炎的免疫调节策略

• 批准号: 6334062
• 负责人: MICHELE M KOSIEWICZ
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334062
• 关键词: CD95 molecule; T cell receptor; T lymphocyte; adenosinetriphosphatase; antigen presenting cell; autoimmune disorder; gastritis; genetically modified animals; immune tolerance /unresponsiveness; immunomodulators; immunotherapy; laboratory mouse; leukocyte activation /transformation; neutralizing antibody; nonhuman therapy evaluation; transforming growth factors

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.

许多自身免疫性疾病似乎是由产生促炎细胞因子 IFNγ 和 TNFα 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巨大的价值。 该拨款提案的目标是研究两种旨在特异性下调抗原特异性 T 细胞活性的策略所涉及的机制，并在已充分表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，在 TGFbeta2 存在的情况下用抗原脉冲的抗原呈递细胞 (APC) 当静脉注射到幼鼠体内时，会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，CD4 和 CD8 调节性 T 细胞在该系统中被诱导并介导抗原特异性耐受。 第一个具体目标是了解 TGFbeta 处理的 APC 诱导耐受的机制。 为此，将使用基因敲除小鼠、中和抗体和 TCR 转基因 T 细胞转移系统在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及其一般作用机制。 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。 第二个具体目标是利用小鼠自身免疫性胃炎模型研究 TGFbeta 处理的 APC 的治疗潜力。 BALB/c 小鼠的新生儿胸腺切除术 (Tx-3) 会诱发与人类恶性贫血明显相似的自身免疫性胃炎。 Tile T 细胞反应在该模型中得到了很好的表征，并且是 Th1 型细胞因子介导的，并靶向壁细胞 H/K ATP 酶的 α 和 β 亚基。 该目的旨在确定用 ATP 酶脉冲的 TGFbeta 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 细胞反应。 第三个具体目标是探索表达 FasL 的 APC 独立治疗自身免疫性疾病的能力或作为 TGFbeta 处理的 APC 治疗的补充。 该目的旨在表征通过用基因工程表达 FasL 的抗原脉冲 APC 进行处理，在体内消除活化的 T 细胞后的 T 细胞反应。该策略可与 TGFbeta 处理的 APC 结合使用，以成功治疗已确定的自身免疫性疾病。