NEGATIVE REGULATION OF AUTOREACTIVE T-CELLS

描述(由申请人提供)：这是一份探索 阿司匹林诱导自身反应性CD4T细胞长期耐受的机制 可溶性MHC II/Fc/多肽嵌合体。我们的初步结果表明， MHC II/Fc/肽嵌合体对糖尿病前期小鼠的短期治疗 调节机制负责对自身抗原的耐受性，以及 提供长达8个月的预防疾病发作的保护。使用 胰岛素依赖型糖尿病双转基因小鼠模型的建立 其中针对已定义自身表位的自身反应性T细胞不是 通过胸腺选择删除，并且它们在外周不被容忍，我们 建议探索MHC诱导的细胞和分子机制 II/Fc/肽嵌合体导致抗原特异性长期耐受。 抗原特异性耐受对免疫显性自身反应的操纵 在新生儿生活中的表位，可能很快就会导致旨在 阻止自身免疫性疾病中的表位扩散。破译 这些机制的细胞和分子基础也可能提供更好的 理解为什么抗原特异性的长期耐受很容易 在新生儿生活中诱导，但在成年生活中不诱导。在…的第一部分 在这一应用中，我们将(1)研究MHC II/Fc/多肽的能力 嵌合体诱导保护性Th2记忆反应和调节/抑制因子 细胞在特定的年龄窗口，(2)表征免疫表型和 在功能上，这些细胞在成年期的命运，和(3)定义它们的 双转基因IDDM对自身免疫性糖尿病的保护作用 老鼠模型。在第二部分中，我们将(1)探索生物化学的本质 几个可以不同的转导和转录事件 在生命早期由MHC II/Fc/多肽嵌合体诱导，这可能会影响 成年后Th2和调节/抑制细胞的命运，以及(2)调查 调控/抑制因子诱导的耐受信号的生化性质 靶器官中自身反应性T细胞中的细胞。令人满意的结果 这项研究将扩大我们对人类MHC的研究领域 携带免疫显性自身反应表位的II/Fc/多肽类试剂 与人类自身免疫性疾病相关。沙门氏菌的抗原特异性耐受性 这些试剂将在体外系统和双转基因系统中进行评估。 小鼠缺乏小鼠MHC-II类，并表达人类人类白细胞抗原-DR* 等位基因。

DESCRIPTION (provided by applicant): This is a proposal to explore the mechanisms of long-term tolerance of autoreactive CD4 T-cells induced by soluble MHC II/Fc/peptide chimeras. Our preliminary results indicated that short therapy with MHC II/Fc/peptide chimeras of prediabetic mice induced regulatory mechanisms responsible for tolerance to a self autoantigen, and offered protection against the disease onset for as long as 8 months. Using a double transgenic mouse model for insulin-dependent diabetes mellitus (IDDM) in which the autoreactive T-cells specific for a defined self epitope were not deleted by thymic selection, and they were not tolerized in periphery, we propose to explore the cellular, and molecular mechanisms induced by MHC II/Fc/peptide chimera leading to antigen-specific long-term tolerance. Manipulation of the antigen-specific tolerance to immunodominant autoreactive epitopes in the neonatal life, may soon lead to novel strategies aimed at arresting the epitope spreading in autoimmune diseases. Deciphering the cellular and molecular basis of these mechanisms may also offer a better understanding of why antigen-specific long-term tolerance can be easily induced in the neonatal life, but not in the adult life. In the first part of this application we will (1) investigate the ability of MHC II/Fc/peptide chimera to induce protective Th2 memory responses and regulatory/suppressor cells during particular age-windows, (2) characterize immunophenotypically and functionally the fate of these cells in adulthood, and (3) define their protective capacity against autoimmune diabetes in the IDDM double transgenic mouse model. In the second part, we will (1) explore the biochemical nature of several transductional and transcriptional events that can be differentially induced by MHC II/Fc/peptide chimera in early life, and that may affect the fate of Th2 and regulatory/suppressor cells in adulthood, and (2) investigate the biochemical nature of tolerogenic signals induced by regulatory/suppressor cells in the autoreactive T-cells in the target organ. Satisfactory results of this study will expand our area of investigations on the human MHC II/Fc/peptide-like reagents carrying immunodominant autoreactive epitopes relevant for human autoimmune diseases. The antigen-specific tolerogenicity of these reagents will be evaluated in in vitro systems, and in double transgenic mice deficient for the murine MHC class II, and expressing human HLA-DR* alleles.