IRF4-dependent T-cell effector programs in governing transplant outcomes

IRF4 依赖性 T 细胞效应程序控制移植结果

基本信息

批准号：
10381743
负责人：
Wenhao Chen
金额：
$ 40.38万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-01-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381743
关键词：
Affect Alloantigen Allogenic Allografting Binding CD4 Positive T Lymphocytes CTLA4 gene Cell Death Cell Transplantation Cell physiology Cells Chromatin Clinical Data Enhancers Epigenetic Process Functional disorder Gene Expression Genes Genetic Transcription Graft Rejection Hematopoietic IRF4 gene Immune Immunity Immunosuppressive Agents Knockout Mice MAP2K1 gene Mediating Modeling Mus Organ Transplantation Outcome PD-L1 blockade PLAGL1 gene Pathway interactions Patients Publications Regulatory Element Regulatory T-Lymphocyte Role Signal Transduction Skin graft Solid T cell regulation T cell response T-Cell Activation T-Lymphocyte Therapeutic immunosuppression Transcriptional Regulation Transplantation Transplantation Tolerance base conditional knockout effector T cell end-stage organ failure epigenetic regulation genome editing graft function heart allograft immune checkpoint blockade in vivo insight post-transplant programmed cell death ligand 1 programmed cell death protein 1 programs response side effect success transcription factor transplant model

项目摘要

Project Summary Solid organ transplantation is a lifesaving treatment for patients with end-stage organ failure, but long- term allograft survival is limited by immune rejection and side effects of immunosuppressive drugs. Allogeneic T cell responses are central to transplant outcomes (rejection versus tolerance). It is thus essential to define the T cell effector programs that affect the transplant outcomes. We recently discovered that interferon regulatory factor 4 (IRF4) is a key transcriptional determinant controlling allogenic T cell response in transplantation. IRF4 deletion in T cells results in progressive establishment of CD4+ T cell dysfunction and long-term cardiac allograft survival. These findings have been accepted for publication in Immunity. Herein, we hypothesized that IRF4 governs transplant outcomes through controlling the core regulatory circuits of T cell function. Therefore, the central focus of this proposal is to identify the IRF4 controlled regulatory circuits in alloreactive effector T cells.

项目摘要固体器官移植是针对末期器官衰竭患者的救生治疗术语同种异体移植生存受到免疫排斥和免疫抑制药物的副作用的限制。同种异体T细胞反应对移植预后（排斥与公差）至关重要。因此定义影响移植结果的T细胞效应程序必不可少的。我们最近发现干扰素调节因子4（IRF4）是关键的转录决定因素控制移植中的同种异体T细胞反应。 T细胞中的IRF4缺失导致渐进式建立CD4+ T细胞功能障碍和长期心脏同种异体移植存活。这些发现有被接受以免疫发表。在此，我们假设IRF4控制移植通过控制T细胞功能的核心调节回路的结果。因此，中心重点该建议的是确定同种异体效应T细胞中的IRF4控制的调节回路。