Immunomodulation by MHC Class II Peptides

描述(逐字摘自申请人的摘要)改进的成功 在过去的十年里，移植物的存活率提高了人们对 经典免疫抑制的长期并发症，因此关注未来 耐受性策略的发展研究。它已经变得显而易见 这些多肽在决定T细胞对 同种异体抗原。这使得人们对其潜在用途的兴趣日益浓厚 合成多肽来操纵T细胞对外来抗原的反应。肽类 从MHC的多态和非多态区域派生的 显示显著影响动物模型中同种异体移植的存活率，以及 在人类身上使用非多态MHC多肽的临床试验目前正在进行 正在进行中。我们的初步数据表明，非多态的MHC II类 衍生的多肽抑制自身抗原的增殖反应，并且 同种异体抗原由直接途径和间接途径递呈。这些 免疫调节作用是通过缺失抗原来实现的。 呈现细胞和T细胞无反应。我们假设 抑制肽通过与MHC-II类分子结合介导其效应， 破坏TCR与MHC+肽复合体的相互作用 调节免疫反应。 该研究计划的目的是研究其作用机制。 介导这些多肽的免疫调节作用并测定它们的 在预防同种异体移植排斥反应中的作用。我们将定义通向 诱导抗原提呈细胞的凋亡，并确定 不同专业抗原提呈细胞的相对敏感性 到删除。无反应性T细胞中的T细胞信号模式 调查和研究，以确定是否缺乏T细胞 对后续刺激的反应是通过无能、缺失或免疫来调节的 偏差。多肽抑制的序列特异性将是 通过氨基酸替换进行评估。将进行约束性研究，以 确定结合的位置和 原始的和改变的多肽。非多态MHC II类分子的能力 将对延长同种异体移植物存活和诱导耐受的多肽进行评估 在小鼠心脏移植模型中。将多肽构建物基因转移到 将进行同种异体心脏移植以调查局部移植的益处。 对比全身给药对移植物存活率的影响。长效的调节机制 同种异体移植物的存活率将在体外和体内进行研究。多肽将是 与其他免疫调节剂联合开发新的耐受策略。 这些研究将有助于阐明MHC-II类肽的潜在作用。 在预防移植排斥反应和诱导免疫耐受方面。

DESCRIPTION (Verbatim from the applicant's abstract) The success of improved graft survival over the last decade has heightened the awareness of the long-term complication of classical immunosuppression, hence focusing future research on the development on tolerogenic strategies. It has become apparent that peptides play a central role in determining T cell responses to alloantigen. This has lead to an increasing interest in the potential use of synthetic peptides to manipulate T cell responses to foreign antigen. Peptides derived from both polymorphic and non-polymorphic regions of the MHC have been shown to significantly impact allograft survival in animals models, and clinical trials using non-polymorphic MHC peptides in humans are currently underway. Our preliminary data demonstrates that non-polymorphic MHC class II derived peptides inhibit the proliferative response to autoantigen, and alloantigen presented by both direct and indirect pathways. These immunomodulatory effects are mediated through the deletion of antigen presenting cells and T cell unresponsiveness. We hypothesize that the inhibitory peptides mediate their effects through binding to MHC class II, disrupting the interaction of the TCR with the MHC+peptide complex and thereby modulating the immune response. The aims of the research proposal are to investigate the mechanism of action mediating the immunomodulatory effects of these peptides and to determine their role in preventing allograft rejection. We will define the pathways leading to the induction of apoptosis in antigen presenting cells and determine the relative susceptibility of the different professional antigen presenting cells to deletion. T cell signaling patterns in unresponsiveness T cells will be investigated, and studies performed to determine whether the lack of T cell response to subsequent stimulation is mediated by anergy, deletion or immune deviation. The sequence specific nature of inhibition by the peptides will be evaluated by amino acid substitutions. Binding studies will performed to determine both the site of binding, and the relative binding affinity of the original and altered peptides. The ability of non-polymorphic MHC class II peptides to prolong allograft survival and induce tolerance will be evaluated in a mouse cardiac transplant model. Gene transfer of peptide constructs to cardiac allografts will be performed to investigate the benefits of local versus systemic delivery on graft survival. The mechanisms mediating long-term allograft survival will be investigated in vitro and in vivo. Peptides will be combined with other immunomodulators to develop novel tolerogenic strategies. These studies will help elucidate the potential role of MHC class II peptides in the prevention of transplant rejection and the induction of tolerance.