NEGATIVE REGULATION OF AUTOREACTIVE T-CELLS

描述（由申请人提供）： 这是一个探讨 诱导自身反应性CD 4 T细胞长期耐受的机制 可溶性MHC II/Fc/肽嵌合体。我们的初步结果表明， 用MHC II/Fc/肽嵌合体诱导的糖尿病前期小鼠的短期治疗 负责对自身自身抗原耐受的调节机制，和 提供了长达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 其中对确定的自身表位特异性的自身反应性T细胞不 删除胸腺选择，他们没有耐受的外围，我们 拟探讨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性。 对免疫显性自身反应的抗原特异性耐受的操纵 表位在新生儿的生活，可能很快导致新的战略，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 了解为什么抗原特异性长期耐受可以很容易地 在新生儿期诱导，但在成年期不诱导。第一部分 本申请我们将（1）研究MHC II/Fc/肽的能力， 嵌合体诱导保护性Th 2记忆应答和调节/抑制 在特定年龄窗期间的细胞，（2）表征免疫表型， 这些细胞在成年期的命运，以及（3）定义它们的功能。 胰岛素依赖型糖尿病双转基因小鼠对自身免疫性糖尿病的保护能力 小鼠模型在第二部分中，我们将（1）探索生物化学的本质， 几个转导和转录事件，可以差异 诱导的MHC II/Fc/肽嵌合体在生命早期，这可能会影响 Th 2和调节/抑制细胞在成年期的命运，以及（2）研究 调节/抑制因子诱导的致耐受性信号的生物化学性质 靶器官中的自身反应性T细胞。合格的食物样本 这项研究将扩大我们的领域 对人类MHC的研究 携带免疫显性自身反应性表位的II/Fc/肽样试剂 与人类自身免疫性疾病有关。的抗原特异性耐受原性 这些试剂将在体外系统中进行评价， 小鼠MHCII类缺陷，并表达人HLA-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.