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.

此申请请求 NEI 多样性研究补充资金以积极的 NEI 赠款（NEI： #EY030283）响应 PA-21-071，支持研究生的研究培训和职业发展 来自贫困种族/民族和经济背景的学生 在拟议的多样性补充中， 博士前研究生将领导一个与以下项目直接相关且互补的具体项目： 与母校 NEI 奖项明显不同。多样性补充提案是为毕业生量身定制的。 学生有兴趣了解 FoxP3+ T 调节细胞 (Treg) 细胞如何与这一过程相互作用 传统的 T 细胞耗竭是维持正常状态所需的非冗余 CD4 T 细胞群。 此外，功能性 Tregs 的缺乏已被证明会导致自我耐受。 我们的研究小组发现了一种在体内操纵 Treg 细胞的新策略。 Tregs 组成型表达 TNFRSF25 受体，我们已经了解到，使用靶向 TNFRSF25 受体的激动剂 并与体内给予的低剂量 IL-2 结合向该受体发出信号，诱导快速且显着的 因此，这种方法提供了一种独特的工具来直接解决问题。 移植领域悬而未决的关键问题是耐受和排斥过程的核心：Tregs 会做吗？ 这个问题对于制定新的预防策略至关重要。 同种异体移植组织排斥，即导致移植抗原特异性 T 细胞耗尽。 接受研究培训和职业发展指导，研究生将学会如何就业 严谨的科学推理和多种技术解决以下两个问题：1）做激活 抗原特异性 CD8 T 细胞诱导之前/期间的 Treg 细胞会改变耗竭过程吗？2) Treg 细胞能否改变？ 细胞会延长排斥反应，而 CD8 耗竭是由抗原驱动的？学生会采取精心设计的方法吗？ 专为博士培训以及参与精心策划的职业技能活动而设计的课程。 学生将与指导团队合作制定个人职业发展计划（IDP） 个性化指导计划（IMP）指导他完成独立的培训过程 以及一位在免疫学和移植领域进行跨学科研究的富有创造力的学者。 研究和职业培训，学生不仅有望推动自己的科学发展 职业生涯，但也做好充分准备，以创造性的解决方案和科学的方式应对新出现的挑战 专业精神推动社会进步。