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.

项目总结