SYNTHETIC INHIBITORS OF CD8+T CELLS IN TRANSPLANTATION

移植中 CD8 T 细胞的合成抑制剂

• 批准号: 6497316
• 负责人: Robert Korngold
• 金额: $ 33.4万
• 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/6497316
• 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.

CD 8 + T细胞在大多数涉及MHC I类或多个次要组织相容性抗原（miHA）差异的移植反应中起重要作用。 CD 8分子作为T细胞受体（TCR）识别由适当抗原呈递细胞上的MHC I类分子呈递的肽抗原的辅助受体发挥作用。 我们最近使用合成肽类似物映射方法来研究CD 8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CD 8+细胞毒性T淋巴细胞（CTL）的活化和效应子功能具有抑制活性，因此在同种异体移植环境中具有作为新的免疫调节剂的潜力。 在这方面，我们将研究这些CD 8抑制剂在两种移植方式-皮肤同种异体移植排斥反应和移植物抗宿主病（GVHD）中的疗效和作用机制。 皮肤同种异体移植物被认为是几种类型的实体器官移植中发生的经典排斥过程的代表性模型。 GVHD是临床异基因骨髓移植（BMT）的主要并发症，通常是致命的。 GVHD的风险可以通过骨髓供体和受体的HLA匹配来降低，匹配的兄弟姐妹是首选。 然而，即使在这种情况下，GVHD仍然普遍存在（50- 60%的发病率），特别是由于次要组织相容性抗原（miHA）的差异，这些抗原能够产生强烈的CD 8 + T细胞应答。 在本提案中，我们的具体目标是：（1）确定从CD 8 α分子的CDR 2和DE环表面设计的抑制剂在皮肤同种异体移植物和GVHD临床前模型中的功效;（2）确定CD 8抑制剂的作用机制;和（3）评价用抑制剂治疗后GVHD模型中BMT受体的免疫活性状态。