T cell fate decisions and transplant outcomes

T 细胞命运决定和移植结果

• 批准号: 10077820
• 负责人: Xian Chang Li
• 金额: $ 40.38万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-10 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077820
• 关键词: Address; Affect; Allograft Tolerance; Allografting; Apoptosis; Area; Autoimmune Diseases; Biological Assay; Bone Marrow Transplantation; Cells; Cessation of life; ChIP-seq; Chromatin; Chronic; Clinic; Clinical; Coupled; Development; Disease; Enhancers; Ensure; Epigenetic Process; Experimental Models; FOXP3 gene; Goals; Graft Survival; Graft Tolerance; Heart Transplantation; Helper-Inducer T-Lymphocyte; Homebound Persons; Immune; Immunity; Immunocompromised Host; Immunosuppression; Inflammation; Inflammatory; Interleukin-4; Interleukin-9; Knockout Mice; Knowledge; Life; Mediating; Modeling; Molecular Genetics; Mus; OX40; Organ Transplantation; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Procedures; Protocols documentation; Regulatory T-Lymphocyte; Reporter; Resistance; Role; Savings; Signal Transduction; Structure; T-Lymphocyte; Testing; Th2 Cells; Therapeutic immunosuppression; Tissues; Toxic effect; Transforming Growth Factor beta; Transplant Recipients; Transplantation; Wood material; base; cancer immunotherapy; cofactor; conditional knockout; cost; cytokine; design; effector T cell; fundamental research; genetic approach; improved; inhibitor/antagonist; insight; memory CD4 T lymphocyte; novel; novel therapeutics; programs; response; theories; therapeutic target; tool; transcription factor; transplant model; transplantation therapy

Project Summary Rejection remains a major hurdle to long-lasting transplant survival. From a clinical standpoint current immunosuppression protocols are fantastic in short-term transplant survival, but do little in promoting long- term graft outcomes. Thus, there is a pressing need to uncover effector programs that may emerge under broad immunosuppressive conditions that can mediate graft loss, with a goal of further improving long term transplant outcomes. We recently discovered that unlike other Th subsets, Th9 cells are robustly induced in an immunosuppressive milieu, suggesting that Th9 cells may be especially relevant to graft loss under conditions of immunosuppression. Th9 cells are induced in massive numbers when the default Th1/Th2 programs are inhibited and require the formation of super-enhancers at Il9 locus (not lineage specific transcription factors). Importantly, formation of Il9 super-enhancers requires OX40 signaling. Also, OX40 is remarkably potent in redirecting Foxp3+ Tregs to inflammatory Th9 cells. Based on the unexpected potency of OX40 in robust Th9 induction, as well as the unexpected mode of actions of OX40 stimulation, we propose to test a unifying hypothesis in this proposal, namely- suppression of the default T cell programs in an immunosuppressive milieu allows OX40 to promote alternative Th9 programs in triggering rejection of otherwise tolerant grafts. We propose 3 Aims in this proposal. Aim 1 focuses on identifying novel mechanisms by which OX40 promotes massive Th9 cells, examining formation, structure, and activities of super-enhancers at Il9 locus. Aim 2 investigates how OX40 redirects Foxp3+ Tregs to Th9 cells, focusing on the newly identified Foxp3 repressors in shutting down Foxp3 expression and examine whether Foxp3 may disrupt IL-9 super enhancer formations. Aim 3 examines the impact of Th9 cells in transplant survival, testing whether targeting super-enhancers or checkpoints in Th9 induction enables robust allograft tolerance. We believe that the proposed studies will unravel new mechanisms of tolerance resistance in transplant recipients, and findings from these studies will have broad impacts on other immune-mediated diseases as well, including cancer immunotherapies and autoimmune diseases.

项目摘要 排斥反应仍然是移植长期存活的主要障碍。从临床角度来看，目前 免疫抑制方案在短期移植存活方面是奇妙的，但在促进长期移植存活方面作用甚微。 定期移植的结果。因此，迫切需要发现可能出现在 广泛的免疫抑制条件，可以调节移植物丢失，目标是进一步改善长期 移植结果。我们最近发现，与其他Th亚群不同，Th9细胞在 免疫抑制的环境，提示Th9细胞可能与移植物丢失特别相关 免疫抑制的条件。当默认Th1/Th2时，Th9细胞被大量诱导 程序被抑制，需要在Il9基因座形成超级增强子(不是谱系特有的 转录因子)。重要的是，IL9超级增强子的形成需要OX40信号。另外，OX40是 在将Foxp3+Tregs重定向至炎性Th9细胞方面非常有效。基于意想不到的力量 OX40在强大的Th9诱导中的作用，以及OX40刺激的意想不到的作用模式，我们 建议检验该提案中的一个统一假设，即-抑制默认T细胞程序 免疫抑制环境允许OX40在触发排斥反应中促进替代Th9计划 否则会有耐受性移植。我们在这项提案中提出了三个目标。目标1专注于识别小说 OX40促进大量Th9细胞形成、结构和活性的机制 IL9基因座的超级增强子。AIM 2研究OX40如何将Foxp3+Tregs重定向至Th9细胞，聚焦 新发现的Foxp3抑制因子在阻断Foxp3表达中的作用 可能会扰乱IL-9超级增强子的形成。AIM 3研究了Th9细胞在移植存活中的影响， 测试针对Th9诱导中的超级增强子或检查点是否能够实现强大的同种异体移植 宽容。我们相信，拟议的研究将揭开人类耐受的新机制。 移植受者，这些研究的结果将对其他免疫介导的 疾病，包括癌症免疫疗法和自身免疫性疾病。