NON-H-2 HISTOCOMPATIBILITY GENES AND ENCODED ANTIGENS

描述（改编自研究者摘要）：轻微 人类和小鼠的组织相容性抗原（HA）构成了一个强大的 刺激同种异体移植物对移植成功的障碍 排斥/功能障碍和移植物抗宿主病。 这些抗原是 临床移植的主要并发症，需要免疫抑制 有其自身的复杂性。 强溶细胞性T淋巴细胞（CTL）应答 免疫显性的小HA不是没有优点，然而，因为它们可能 提供成功的移植物抗白血病反应， 显性次要HA仅限于造血细胞。 本申请中提出的研究首先针对 了解小鼠识别次要HA的分子基础 H4肽和鉴定的模拟表位作为主要模型。 的 提出的实验将检验这一假设，即带正电的 H4中的氨基酸是控制识别的主要因素， H4特异性T细胞受体（TcRs）和H4作为显性免疫调节剂的功能 肽。 提出了三个具体目标。 首先，H4的突变分析 将进行模拟表位和Kb分子鉴定氨基酸 参与模拟表位、Kb结合和TcR识别。 第二、 体内反应中次要HA特异性TcR多样性的演变 多种抗原攻击和长时间暴露于抗原将是 研究了TcR β链多样性的稳定性。 第三、 在次要HA肽和特异性HA肽中的相反电荷残基的作用 体内和体外TcRs对识别和显性抗原功能的影响将 被识别。 这种通过表达的TcR对次要HA肽的识别， CTL在体内发生在处理少量HA的系统的保护伞下 肽并最终破坏同种异体移植物。 最后的目标涉及到 优势机制和同种异体移植排斥反应。 第四个具体目标是 检验支配地位是建立在破坏 通过显性抗原特异性CTL的专职抗原呈递细胞， 排除显性抗原的呈递。 最终目标是 多效性肿瘤坏死因子-a表达对肝癌细胞增殖的影响 细胞因子对皮肤移植物中转录的影响 评估捐赠者和接受者参与的拒绝时间 基因表达在整个过程中。

DESCRIPTION (Adapted from the Investigator's abstract): Minor histocompatibility antigens (HA) in humans and mice constitute a formidable barrier to successful transplantation by stimulating allograft rejection/dysfunction and graft versus host disease. These antigens are a major complication in clinical transplantation, requiring immunosuppression with its own complications. Strong cytolytic T lymphocyte (CTL) responses to immunodominant minor HA are not without virtue, however, since they may provide for successful graft-versus-leukemia responses in cases where dominant minor HA are restricted to hematopoietic cells. The studies proposed in this application are directed first toward understanding the molecular basis for recognition of minor HA with the mouse H4 peptide and identified mimotopes serving as the principal model. The proposed experiments will test the hypothesis that the positively charged amino acid in the H4 is the preeminent factor in controlling recognition by H4-specific T-cell receptors (TcRs) and the function of H4 as a dominant peptide. Three specific aims are proposed. First, mutational analysis of H4 mimotopes and Kb molecules will be performed to identify the amino acids that are involved in mimotopes and Kb binding and TcR recognition. Second, the evolution of diversity of minor HA-specific TcRs in the in vivo response to multiple antigenic challenges and prolonged exposure to antigen will be investigated to evaluate the stability of TcR beta chain diversity. Third, the effects of opposing charged residues in minor HA peptides and specific TcRs on recognition and dominant antigen function in vivo and in vitro will be identified. This recognition of minor HA peptides by TcRs expressed by CTLs occurs in vivo under the umbrella of systems that process minor HA peptides and ultimately destroy allografts. The final aims relate to the mechanisms of dominance and allograft rejection. The fourth specific aim is testing the hypothesis that dominance is based in the destruction of professional antigen presenting cells by dominant antigen-specific CTLs to the exclusion of presentation of dominated antigens. The final aim is the study of the effect of expression of the pleiotropic tumor necrosis factor-a cytokine on transcription in skin allografts from the time of transplants to the time of rejection to assess the participation of donor and recipient gene expression in the entire process.