Immunomodulation by MHC Class II Peptides

MHC II 类肽的免疫调节

• 批准号: 6319235
• 负责人: Barbara T. Murphy
• 金额: $ 28.37万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6319235
• 关键词: B lymphocyte; CD28 molecule; CD40 molecule; MHC class II antigen; T cell receptor; T lymphocyte; apoptosis; binding sites; cell proliferation; cyclosporines; delayed hypersensitivity; dendritic cells; disease /disorder model; gene targeting; genetically modified animals; heart transplantation; homologous transplantation; immunoregulation; isoantigen; laboratory mouse; macrophage; plasmids; sirolimus; synthetic peptide; transplantation immunology

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.

描述（申请人摘要的逐字记录）改进的成功 过去十年的移植物存活率提高了人们的认识 经典免疫抑制的长期并发症，因此关注未来 耐受策略开发的研究。已经很明显了 肽在决定 T 细胞反应方面发挥着核心作用 同种异体抗原。这导致人们对潜在用途越来越感兴趣 合成肽来操纵 T 细胞对外来抗原的反应。肽 源自 MHC 的多态性和非多态性区域 在动物模型中显示显着影响同种异体移植物的存活率，并且 目前正在人体中使用非多态性 MHC 肽进行临床试验 进行。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反应，并且 同种异体抗原通过直接和间接途径呈递。这些 免疫调节作用是通过抗原的缺失介导的 呈递细胞和 T 细胞无反应。我们假设 抑制肽通过与 MHC II 类结合来介导其作用， 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 具有防止同种异体移植排斥反应的作用。我们将定义通往 诱导抗原呈递细胞凋亡并确定 不同专职抗原呈递细胞的相对敏感性 到删除。无反应 T 细胞中的 T 细胞信号传导模式将 进行调查和研究以确定是否缺乏 T 细胞 对后续刺激的反应是由无反应、缺失或免疫介导的 偏差。肽抑制的序列特异性将是 通过氨基酸取代来评价。结合研究将进行 确定结合位点和相对结合亲和力 原始和改变的肽。非多态性MHC II类的能力 将评估延长同种异体移植物存活和诱导耐受性的肽 在小鼠心脏移植模型中。将肽构建体基因转移至 将进行同种异体心脏移植以研究局部心脏移植的益处 与全身给药对移植物存活的影响。长期调节机制 将在体外和体内研究同种异体移植物的存活率。肽将是 与其他免疫调节剂结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 预防移植排斥和诱导耐受。