Immunomodulation by MHC Class II Peptides

描述（申请人摘要的逐字逐句）改进的成功 在过去的十年里，移植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 耐受性策略的研究进展。很明显 肽在决定T细胞对 同种抗原这导致了对潜在用途的兴趣日益增加。 合成肽来操纵T细胞对外来抗原的应答。肽 来自MHC的多态性和非多态性区域， 在动物模型中显示出显著影响同种异体移植物存活， 目前在人体中使用非多态性MHC肽的临床试验 正在进行中我们的初步数据表明，非多态性MHC II类 衍生肽抑制对自身抗原的增殖应答，和 通过直接和间接途径呈递同种异体抗原。这些 免疫调节作用是通过抗原的缺失介导的 提呈细胞和T细胞无反应性。我们假设 抑制性肽通过结合II类MHC介导其作用， 破坏TCR与MHC+肽复合物的相互作用，从而 调节免疫反应。 研究计划的目的是调查作用机制 介导这些肽的免疫调节作用，并确定它们的 预防同种异体移植排斥反应的作用。我们将确定通往 诱导抗原呈递细胞的凋亡，并确定 不同专职抗原呈递细胞的相对易感性 到删除。无反应性T细胞中的T细胞信号传导模式将是 调查，并进行研究，以确定是否缺乏T细胞 对后续刺激的反应由无反应性、缺失或免疫介导。 偏差肽的抑制的序列特异性性质将是 通过氨基酸取代进行评估。将进行结合研究， 确定结合位点和相对结合亲和力。 原始的和改变的肽。非多态性MHC II类分子 将评估延长同种异体移植物存活和诱导耐受的肽 在小鼠心脏移植模型中。将肽构建体的基因转移至 将进行心脏同种异体移植，以研究局部 与全身给药相比对移植物存活的影响。长期调解机制 将在体外和体内研究同种异体移植物存活。肽将 与其他免疫调节剂组合以开发新的致耐受性策略。 这些研究将有助于阐明MHC II类肽的潜在作用， 预防移植排斥和诱导耐受。

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.