Control of Treg exhaustion by OX40

OX40 控制 Treg 耗竭

• 批准号: 8707631
• 负责人: Xian Chang Li
• 金额: $ 27.56万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707631
• 关键词: Acute; Address; Allograft Tolerance; Allografting; Antigens; Apoptosis; Apoptotic; Area; Autoimmune Diabetes; Automobile Driving; Binding; Biology; Bone Marrow Transplantation; Breeding; CD4 Positive T Lymphocytes; Cell Death; Cell surface; Chronic; Clinic; Data; Development; Disease; Down-Regulation; Epigenetic Process; Family; Gene Transfer; Goals; Heart Transplantation; Heterogeneity; Homeostasis; Immune; Immune Tolerance; Immunity; Immunosuppression; Interleukin-10; Interleukin-2; Investigation; Knockout Mice; Lead; Life; Ligation; Malignant Neoplasms; Mediating; Modeling; Mus; Organ Transplantation; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Procedures; Promoter Regions; Regulation; Regulatory T-Lymphocyte; Reporter Genes; Research; Resistance; Role; Self Tolerance; Signal Transduction; Staging; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Transcription Repressor/Corepressor; Transplantation; activating transcription factor; allograft rejection; base; cancer therapy; cell type; cytokine; design; exhaust; exhaustion; functional disability; improved; in vivo; insight; member; novel; novel therapeutics; overexpression; peripheral tolerance; prevent; programs; receptor; retroviral-mediated; senescence; sobriety; transcription factor; tumor necrosis factor receptor superfamily member 4

DESCRIPTION (provided by applicant): With the advent of powerful immunosuppression drugs, acute allograft rejection is rare now in the clinic and the short-term transplant survival hs been excellent. However, long-term transplant survival is also rare and most allografts are continuously lost to rejection as time progresses. This is a sober reminder that there remain significant barriers to graft acceptance. We recently discovered that Foxp3+ Tregs, a cell type dedicated to immune regulation and also critically involved in transplant tolerance, can be driven to an exhausted phenotype by the costimulatory receptor OX40. Such exhausted Tregs readily lose their regulatory functions, acquire typical exhaustion markers such as PD-1, Tim-3, and KLRG1, and become extremely sensitive to apoptosis. Through transcriptional profiling, we identified a new transcription factor, namely Baft3 that is strongly induced by OX40 in Tregs and closely associated with the development of exhausted Tregs. We provide preliminary data that Baft3 physically binds to the promoter region of Foxp3 and actively suppresses Foxp3 expression. Based on this, we hypothesized that Treg exhaustion is an alternative fate of Foxp3+ Tregs and Treg exhaustion is transcriptionally regulated in which Batf3 plays a central role. Understanding the mechanisms of Batf3 induction by OX40 and how Batf3 drives Tregs to exhaustion is the central focus of this application. We believe that the proposed studies will unravel novel mechanisms of tolerance resistance and may lead to the development of new therapies in the induction of transplant tolerance. In addition, findings from these studies will have broad impacts on other immune-mediated diseases, such as cancer therapies and protective immunity.

描述（由申请人提供）：随着强大的免疫抑制药物的出现，急性同种异体移植排斥在诊所中很少见，而短期移植生存率HS非常好。但是，长期移植生存也很少见，并且随着时间的流逝，大多数同种异体移植物不断丢失。这是一个清醒的提醒，即嫁接接受仍然存在重大障碍。我们最近发现，Foxp3+ Tregs是一种专门用于免疫调节的细胞类型，也可以通过严重参与移植耐受性，可以被共刺激受体OX40驱动到耗尽的表型中。如此疲惫的Treg很容易失去其调节功能，获得了典型的疲惫标记，例如PD-1，TIM-3和KLRG1，并对凋亡非常敏感。通过转录分析，我们确定了一种新的转录因子，即BAFT3，该因子是由Treg中OX40强烈诱导的，并且与耗尽的Treg的发展密切相关。我们提供了BAFT3物理结合FOXP3的启动子区域并积极抑制FOXP3表达的初步数据。基于这一点，我们假设Treg Eltion是Foxp3+ Tregs的替代命运，而Treg Eltion是在转录调节中，BATF3起着核心作用。了解OX40诱导BATF3的机制以及BATF3如何使Treg耗尽的耗尽是该应用的中心重点。我们认为，拟议的研究将揭示耐受性抗性的新机制，并可能导致新疗法在诱导移植耐受性时发展。此外，这些研究的发现将对其他免疫介导的疾病（例如癌症疗法和保护性免疫）产生广泛的影响。