Investigation of the Molecular Basis of T Cell Alloreactivity

描述(由申请人提供)：申请者是一名内科科学家，致力于研究与临床相关的问题，目标是发展作为一名独立调查员的职业生涯。通过以移植和临床组织相容性为重点的免疫学和临床病理学培训，候选人已经发展出必要的临床专业知识，以识别与临床相关和具有科学重要性的问题，并将基础科学发现转化为临床医学。在圣路易斯华盛顿大学导师保罗·M·艾伦的帮助下，这位候选人开发了一个研究项目，以解决异基因移植的根本障碍，即T细胞对同种异体主要组织相容性复合体(MHC)分子的强烈初级同种异体反应。虽然人们早就认识到MHC的广泛多态以及MHC通过T细胞受体(TCR)激活T细胞的直接作用使MHC成为移植的主要抗原屏障，但TCR与同种异体MHC之间的分子相互作用仍是一个谜。同种异体反应性对于基础了解T细胞对抗原的识别以及临床同种异体移植都是重要的。申请者和导师假设，同种异体反应性T细胞介导移植物抗宿主病(GvHD)的谱系是由自然表达双重TCR的T细胞扩大的，CDR3的组成对GvHD的特异性或多特异性识别至关重要。为了解决这些问题，申请人建议继续研究TCR谱系在GvHD中的影响；申请人建议将初步结果转换为人体模型，包括诊断测试开发的临床可行性研究。此外，申请人建议检查介导GvHD的T细胞谱系的广度，以确定TCR谱系诱发同种异体反应性的分子决定因素，以及随后的功能研究，以确定TCR与同种异体MHC和呈现肽的关键分子相互作用。总之，这些研究将提高对分子相互作用的理解，确定与GvHD有关的同种异体反应性T细胞反应，使进一步研究和合理设计改进的诊断、免疫抑制剂和供体匹配策略。申请书中提出的工作，加上艾伦博士的指导和华盛顿大学病理学和免疫学系学术界的支持，将使申请者能够发展成为一名独立的研究人员、内科科学家。同种异体反应性T细胞受体谱系的分子定义 项目叙述同种异体MHC的T细胞识别活性是一个重要的研究领域，无论是对T细胞生物学的理解，还是在临床移植成功中都是如此；同种异体MHC的T细胞识别是临床同种异体移植成功的主要障碍，尽管TCR与同种异体MHC和提呈多肽的分子相互作用尚未很好地确定。该项目旨在促进对这些相互作用的分子特征的理解，使随后在固体器官和造血干细胞移植方面的进展成为可能。

DESCRIPTION (provided by applicant): The applicant is a physician-scientist dedicated to investigating clinically-relevant questions with the goal of developing a career as an independent investigator. Through training in immunology and clinical pathology focusing on transplantation and clinical histocompatibility the candidate has developed clinical expertise necessary for discerning clinically-relevant and scientifically important questions and translating basic science findings into clinical medicine. With these skills, the candidate, with help from mentor Paul M. Allen at Washington University in St. Louis, has developed a research project to address the fundamental barrier to allogeneic transplantation, the strong primary alloreactive response of T cells to allogeneic major histocompatibility complex (MHC) molecules. While it has long been recognized that the wide array of polymorphisms in MHC in combination with the direct role of MHC in activation of T cells through the T cell receptor (TCR) makes MHC the primary antigenic barrier to transplantation, the molecular interactions between TCR and allogeneic MHC defining alloreactivity remain enigmatic. Alloreactivity is important both in fundamental understanding of T cell recognition of antigen, as well as in clinical allogeneic transplantation. The applicant and mentor hypothesize that the repertoire of alloreactive T cells mediating graft vs. host disease (GvHD), a highly clinically-relevant manifestation of alloreactivity, is expanded by T cells naturally expressing dual TCRs and that the TCR repertoire involved in GvHD is greatly influenced by CDR3 composition which is critical for specific or polyspecific recognition of presented peptide antigens. To address these questions, the applicant proposes research that continues investigation of the influence of the TCR repertoire in GvHD; the applicant proposes to translate preliminary results demonstrating the participation of highly alloreactive dual TCR T cells in GvHD to human models, including clinical feasibility studies for diagnostic test development. Additionally, the applicant proposes examining the breadth of the repertoire of T cells mediating GvHD, to identify molecular determinants of the TCR repertoire predisposing alloreactivity, and subsequent functional studies to determine critical molecular interactions of the TCR with allogeneic MHC and presented peptides. Together, these studies will improve understanding of molecular interactions defining the alloreactive T cell response responsible for GvHD, enabling further investigation and rational design of improved diagnostics, immunosuppressive agents, and donor matching strategies. The work proposed in this application, in combination with the mentorship of Dr. Allen and the support of the academic community at the Department of Pathology and Immunology at Washington University will enable the applicant to develop into an independent investigator physician scientist. Molecular Definition of the Alloreactive T Cell Receptor Repertoire Project Narrative Alloreactivity, T cell recognition of allogeneic MHC, is an important area of investigation, both for understanding T cell biology, as well as in successful clinical transplantation; T cell recognition of allogeneic MHC is the primary barrier to successful clinical allogeneic transplantation, though the molecular interactions of TCR with allogeneic MHC and presented peptides are not well defined. This project aims to advance understanding of the molecular features of these interactions, enabling subsequent advances in solid organ and hematopoietic stem cell transplantation.