Investigation of the Molecular Basis of T Cell Alloreactivity

描述（由申请人提供）：申请人是一名医生，科学家，致力于调查临床相关问题，目标是发展独立调查员的职业生涯。通过免疫学和临床病理学的培训，重点是移植和临床组织相容性，候选人已经发展了识别临床相关和科学重要问题并将基础科学发现转化为临床医学所需的临床专业知识。有了这些技能，候选人，在导师保罗M。位于圣路易斯的华盛顿大学的艾伦开发了一个研究项目，以解决同种异体移植的基本障碍，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。尽管早已认识到MHC中的广泛多态性与MHC在通过T细胞受体（TCR）活化T细胞中的直接作用相结合使得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定义同种异体反应性仍然是谜。同种异体反应性在理解T细胞识别抗原的基础上，以及在临床同种异体移植中都是重要的。申请人和导师假设，介导移植物抗宿主病（GvHD）（同种异体反应性的一种高度临床相关表现）的同种异体反应性T细胞库被天然表达双重TCR的T细胞扩增，并且GvHD中涉及的TCR库受到CDR 3组成的极大影响，CDR 3组成对于呈递肽抗原的特异性或多特异性识别至关重要。为了解决这些问题，申请人提出继续研究TCR库在GvHD中的影响;申请人提出将初步结果转化为人类模型，包括诊断测试开发的临床可行性研究，这些初步结果证明了高度同种异体反应性双重TCR T细胞在GvHD中的参与。此外，申请人提出检查介导GvHD的T细胞库的宽度，以鉴定TCR库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和呈递肽的关键分子相互作用。总之，这些研究将提高对定义负责GvHD的同种异体反应性T细胞应答的分子相互作用的理解，从而能够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。本申请中提出的工作，结合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，将使申请人能够发展成为一名独立的调查医生科学家。同种异体反应性T细胞受体库的分子定义 同种异体反应性，T细胞识别同种异体MHC，是一个重要的研究领域，无论是为了了解T细胞生物学，以及在成功的临床移植; T细胞识别同种异体MHC是成功的临床同种异体移植的主要障碍，尽管TCR与同种异体MHC和呈递肽的分子相互作用还没有很好地定义。该项目旨在促进对这些相互作用的分子特征的理解，从而实现实体器官和造血干细胞移植的后续进展。

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.