Local regulation and deletion of T cells to induce tolerance and establish long-term survival of high-risk corneal transplants

局部调节和删除 T 细胞以诱导耐受并建立高风险角膜移植物的长期存活

• 批准号: 10655894
• 负责人: Robert Benjamin Levy
• 金额: $ 4.48万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10655894
• 关键词: Address; Agonist; Allografting; Antigens; Automobile Driving; Award; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cornea; Development Plans; Doctor of Philosophy; Dose; Economics; Educational Curriculum; FOXP3 gene; Face; Funding; Grant; Histocompatibility Antigens; Immunology; Individual; Interdisciplinary Study; Interleukin-2; Keratoplasty; Lead; Learning; Maintenance; Mentors; Parents; Pathology; Peripheral; Population; Process; Professional Competence; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Request for Applications; Research; Research Project Grants; Research Support; Research Training; Scientist; Self Tolerance; Societies; Students; T cell regulation; T-Lymphocyte; Technology; Tissues; Training; Transplantation; Work; antigen-specific T cells; career; career development; design; exhaustion; graduate student; high risk; in vivo; interest; novel strategies; pre-doctoral; prevent; racial and ethnic; receptor; response; tool; underrepresented minority student

This application requests the NEI diversity research supplement funding to an active NEI grant (NEI: #EY030283) in response to PA-21-071, to support the research training and career development of a graduate student from an underprivileged racial/ethnic and economic background. In the proposed diversity supplement, a predoctoral graduate student will lead a specific project that is directly relevant and complementary to - yet clearly distinct from - the parent NEI award. The diversity supplement proposal is tailored for the graduate student’s interest to understand how FoxP3+ T regulatory cells (Tregs) cells interact with the process of conventional T cell exhaustion. Tregs are a non-redundant CD4 T cell population required for the maintenance of self-tolerance. Additionally, the lack of functional Tregs has been demonstrated to result in lymphoproliferation and pathology. Our group has discovered a novel strategy to manipulate Treg cells in vivo. Tregs constitutively express the TNFRSF25 receptor, and we have learned that using agonists which target and signal this receptor in combination with low doses of IL-2 administered in vivo, induce a rapid and marked increase in the peripheral Treg compartment. Hence, this approach provides a unique tool to directly address a key unanswered question in the transplant field central to the process of tolerance and rejection: do Tregs impact the process of T cell exhaustion. This question is critical to develop a novel strategy to prevent allografted tissue rejection, that is driving transplant antigen specific T cells to exhaustion. Specifically, while undergoing research training and career development mentoring, the graduate student will learn to employ rigorous scientific reasoning and multiple technologies to address the follow two questions: 1) Do activated Treg cells prior/during induction of antigen specific CD8 T cells alter the exhaustion process? and 2) Can Treg cells prolong rejection while CD8 exhaustion is driven by antigen? The student will take a well-crafted curriculum designed for PhD training as well as participate in well-orchestrated career skill activities. The student will work with a mentoring team to develop an individual career development plan (IDP) and individualized mentoring plan (IMP) to guide him through the training process towards becoming independent and a creative scholar conducting interdisciplinary research in immunology and transplantation. Through the research and career training, the student is expected to be not only endowed to advance their own scientific career, but also well-prepared to face emerging challenges with creative solutions and scientific professionalism to advance society.

本申请要求NEI多样性研究补充资金，以积极NEI赠款（NEI： #EY030283）响应PA-21 - 071，以支持研究培训和毕业生的职业发展 来自贫困种族/民族和经济背景学生。在拟议的多样性补充中， 一名博士前研究生将领导一个直接相关和互补的具体项目， 明显区别于-父母NEI奖。多样性补充提案是为毕业生量身定制的 学生的兴趣，以了解如何FoxP3 + T调节细胞（T细胞）细胞相互作用的过程中， 常规T细胞耗竭。T细胞是维持免疫系统所需的非冗余CD4 T细胞群。 自我宽容。此外，已证明缺乏功能性T细胞会导致 淋巴增生和病理学。我们的团队已经发现了一种在体内操纵Treg细胞的新策略。 TNF-α组成型表达TNFRSF25受体，我们已经了解到，使用靶向TNF-α的激动剂， 并将该受体与体内施用的低剂量IL-2组合，诱导快速且显著的 外周Treg区室增加。因此，这种方法提供了一种独特的工具来直接解决 在移植领域，对耐受和排斥过程至关重要的一个关键的未回答的问题： 影响T细胞耗竭的过程。这个问题对于开发一种新的预防策略至关重要 同种异体移植组织排斥，这是驱动移植抗原特异性T细胞耗尽。具体地说，虽然 通过研究培训和职业发展指导，研究生将学会就业 严谨的科学推理和多种技术解决了以下两个问题：1）激活 抗原特异性CD8 T细胞诱导前/诱导期间的Treg细胞改变耗竭过程？和2）Can Treg 细胞延长排斥反应，而CD8耗竭是由抗原驱动的？学生将采取精心制作的 为博士培训设计的课程，以及参加精心策划的职业技能活动。的 学生将与辅导团队合作，制定个人职业发展计划（IDP）， 个性化辅导计划（IMP），指导他通过培训过程变得独立 一位富有创造力的学者，从事免疫学和移植的跨学科研究。通过 研究和职业培训，学生不仅有望被赋予推进自己的科学 职业生涯，但也准备好面对新的挑战与创造性的解决方案和科学 以专业精神推动社会进步。