SYNTHETIC INHIBITORS OF CD8+T CELLS IN TRANSPLANTATION

移植中 CD8 T 细胞的合成抑制剂

• 批准号: 6046145
• 负责人: Robert Korngold
• 金额: $ 31.74万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6046145
• 关键词: CD8 molecule; Orthomyxoviridae; biological signal transduction; bone marrow transplantation; clinical research; cyclosporines; cytokine; cytotoxic T lymphocyte; disease /disorder model; dosage; drug screening /evaluation; graft versus host disease; human subject; immunosuppressive; immunotherapy; laboratory mouse; skin transplantation; synthetic peptide; transplantation immunology

CD8+ T cells play an important role in most transplantation reactions involving either MHC class I or multiple minor histocompatibility antigen (miHA) disparities. The CD8 molecule functions as a coreceptor for the T cell receptor (TCR) recognition of peptide antigens presented by MHC class I molecules on an appropriate antigen presenting cell. We have recently used a synthetic peptide analog mapping approach to study the structure/function relationship of the surfaces of CD8, and have unveiled sites potentially involved in class I MHC binding. Synthetic peptide mimics of these interactive sites appear to have inhibitory activity on the activation and effector function of CD8+ cytotoxic T lymphocytes (CTL) and therefore have potential as new immunoregulatory agents in allogeneic transplantation settings. In this regard, we will investigate the efficacy and mechanism of action of these CD8 inhibitors in two transplantation modalities - skin allograft rejection and graft-versus-host disease (GVHD). Skin allografts are recognized as a representative model for the classic rejection processes that occur in several types of solid organ transplantation. GVHD is a major, and often lethal, complication of clinical allogeneic bone marrow transplantation (BMT). The risk of GVHD can be reduced by HLA-matching of the marrow donor and recipient, with a matched sibling being the primary choice. However, even in this case GVHD is still prevalent (50-60 percent incidence), particularly due to disparities in minor histocompatibility antigens (miHA), which are capable of generating strong CD8+ T cell responses. In this proposal our specific aims are to: (1) determine the efficacy of inhibitors designed from the CDR2 and DE-loop surfaces of the CD8alpha molecule in the skin allograft and GVHD preclinical models; (2) determine the mechanism of action of the CD8 inhibitors; and (3) evaluate the immunocompetent status of BMT recipients in the GVHD models after treatment with the inhibitory agents.

CD8+ T细胞在大多数涉及MHC I类或多种次要组织相容性抗原（miHA）差异的移植反应中发挥重要作用。CD8分子作为T细胞受体（TCR）识别由MHC I类分子在合适的抗原呈递细胞上呈递的肽抗原的辅助受体。我们最近使用合成肽类似物作图方法来研究CD8表面的结构/功能关系，并揭示了可能参与I类MHC结合的位点。这些相互作用位点的合成肽模拟物似乎对CD8+细胞毒性T淋巴细胞（CTL）的激活和效应功能具有抑制活性，因此有可能在同种异体移植环境中作为新的免疫调节剂。在这方面，我们将研究这些CD8抑制剂在两种移植模式——皮肤同种异体移植排斥和移植物抗宿主病（GVHD）中的疗效和作用机制。同种异体皮肤移植被认为是发生在几种类型的实体器官移植中的典型排斥过程的代表模型。GVHD是临床同种异体骨髓移植（BMT）的主要并发症，通常是致命的。骨髓供体和受体的hla匹配可以降低GVHD的风险，匹配的兄弟姐妹是首选。然而，即使在这种情况下，GVHD仍然很普遍（50- 60%的发病率），特别是由于次要组织相容性抗原（miHA）的差异，它能够产生强烈的CD8+ T细胞反应。在这个提议中，我们的具体目标是：(1)确定从cd8 α分子的CDR2和DE-loop表面设计的抑制剂在同种异体皮肤移植和GVHD临床前模型中的功效；(2)确定CD8抑制剂的作用机制；(3)评价GVHD模型BMT受体在抑制剂治疗后的免疫功能状态。