SYNTHETIC INHIBITORS OF CD8+T CELLS IN TRANSPLANTATION

CD8T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着重要作用。CD8分子作为T细胞受体(TCR)识别MHC-I类分子在合适的抗原提呈细胞上提呈的多肽抗原的辅助受体。我们最近使用了一种合成肽类似图谱的方法来研究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。这些相互作用部位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，因此有可能成为异基因移植环境中的新的免疫调节剂。在这方面，我们将研究这些CD8抑制剂在两种移植方式-皮肤移植排斥反应和移植物抗宿主病(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固体器官移植中的典型排斥过程的典型模型。移植物抗宿主病(GVHD)是临床异基因骨髓移植(BMT)的一种主要且往往致命的并发症。骨髓供受者的人类白细胞抗原配型可以降低移植物抗宿主病的风险，配对的兄弟姐妹是首要选择。然而，即使在这种情况下，移植物抗宿主病仍然很普遍(50%-60%)，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CD8T细胞反应。在这项建议中，我们的具体目标是：(1)确定根据CD8α分子的CDR2和DE环表面设计的抑制剂在同种异体皮肤移植和GVHD临床前模型中的有效性；(2)确定CD8抑制剂的作用机制；(3)评估骨髓移植受者在GVHD模型中接受抑制药物治疗后的免疫活性状态。

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.