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CD27/CD70 mediated negative regulation of inflammatory T cell responses

CD27/CD70 介导的炎症 T 细胞反应的负调节

基本信息

批准号：
10226021
负责人：
Xuefang Cao
金额：
$ 58.61万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226021
关键词：
Affect Allogenic Antibodies Antigen-Presenting Cells Antigens Cell surface Cells Chimera organism Complex Complication Exhibits Family member Hematological Disease Hematopoietic Human ITGAX gene Immune System Diseases In Vitro Incidence Infection Inflammatory Lead Ligands Lymphocyte MHC antigen Mediating Memory Metabolism Modeling Morbidity - disease rate Mus Normal tissue morphology Organ Pathway interactions Patients Play Quality of life Regulation Regulatory T-Lymphocyte Resistance Role Severities Signal Transduction Signal Transduction Pathway Specific qualifier value T cell response T-Cell Activation T-Lymphocyte TNFRSF1A gene Testing Therapeutic immunosuppression Up-Regulation Virus Diseases Xenograft procedure base clinically relevant curative treatments cytokine cytotoxic design exhaustion graft vs host disease hematopoietic cell transplantation improved in vivo innovation migration mortality mouse model novel novel strategies overexpression therapeutic evaluation

项目摘要

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for a variety of hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) remains the major complication that causes significant morbidity and mortality despite the currently practiced immunosuppressive therapies. GVHD is known to be caused by donor-derived T cells that recognize allogeneic antigens expressed on host cells and subsequently damage host normal tissues. In addition to TCR signaling stimulated by MHC- antigen complex, co-stimulatory pathways are involved in T cell activation and function. The co-stimulatory molecule CD27 is a TNF receptor family member expressed on T cells and its ligand, CD70, is known to be expressed on activated antigen-presenting cells (APC) as well as T cells. Previous studies using mainly viral infection models have largely described this pathway as “stimulatory” and required for optimal T cell responses, while its role in allo-HCT is previously unknown. In this project, we have used established murine models to study the roles of CD27/CD70 in GVHD. Our results reveal a novel inhibitory role played by this pathway as specified in 2 aspects: 1) allo-HCT shows that both CD27-/- and CD70-/- donor T cells caused more severe GVHD than WT donor T cells, suggesting that CD27/CD70 signaling in donor T cells inhibits allogeneic T cell response; 2) when used as hosts for allo-HCT, both CD27-/- and CD70-/- mice exhibited more severe GVHD compared to WT hosts, suggesting that CD27/CD70 signaling in the host inhibits allogeneic T cell response. Initial mechanistic analyses suggest that this pathway inhibits GVHD by limiting donor T cell expansion and reducing pro-inflammatory cytokines in a donor regulatory T cell-independent fashion. Based on these results, our central hypothesis is that CD27/CD70 signaling plays a novel role suppressing GVHD by inhibiting allogeneic inflammatory T cell response. We propose three aims to systematically pursue donor T cell-derived mechanisms, host-derived mechanisms and clinical relevance of this pathway in the context of GVHD. Understanding such mechanisms will be critical for developing innovative strategies that can control GVHD and improve quality of life for allo-HCT patients.

异基因造血细胞移植（allo-HCT）是一种潜在的治愈性治疗各种疾病的方法。血液和免疫疾病。然而，移植物抗宿主病（GVHD）仍然是主要的尽管目前使用免疫抑制剂，治疗已知GVHD是由供体来源的T细胞引起的，其识别表达的同种异体抗原。并随后损害宿主正常组织。除了由MHC刺激的TCR信号外，抗原复合物，共刺激途径参与T细胞活化和功能。共刺激分子CD 27是在T细胞上表达的TNF受体家族成员，并且已知其配体CD 70是在活化的抗原呈递细胞（APC）以及T细胞上表达。以前的研究主要使用病毒感染模型在很大程度上将该途径描述为“刺激性的”，并且是最佳T细胞增殖所必需的。反应，而其在allo-HCT中的作用以前是未知的。在这个项目中，我们已经建立了小鼠研究CD 27/CD 70在GVHD中的作用。我们的研究结果揭示了一个新的抑制作用，发挥这一点，途径如2个方面所述：1）allo-HCT显示CD 27-/-和CD 70-/-供体T细胞引起更多严重的GVHD比WT供体T细胞，这表明供体T细胞中的CD 27/CD 70信号传导抑制同种异体移植物抗宿主病。 T细胞反应; 2）当用作allo-HCT的宿主时，CD 27-/-和CD 70-/-小鼠均表现出更严重的T细胞反应。 GVHD与WT宿主相比，表明宿主中的CD 27/CD 70信号传导抑制同种异体T细胞增殖。反应初步的机制分析表明，该途径通过限制供体T细胞的增殖来抑制GVHD。扩增并以供体调节性T细胞非依赖性方式减少促炎细胞因子。基于根据这些结果，我们的中心假设是，CD 27/CD 70信号转导通过以下途径在抑制GVHD中发挥新的作用：抑制同种异体炎性T细胞应答。我们提出了三个目标，系统地追求捐助者T 细胞来源的机制，宿主来源的机制和临床相关性，这一途径的背景下， GVHD。了解这些机制对于制定创新战略， GVHD和改善allo-HCT患者的生活质量。