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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.

同种异体造血细胞移植（allo-HCT）是一种潜在的治疗多种造血干细胞移植的方法。血液学和免疫学疾病。然而，移植物抗宿主病（GVHD）仍然是主要的尽管目前采用免疫抑制治疗，但仍导致显着发病率和死亡率的并发症疗法。 GVHD 已知是由供体来源的 T 细胞引起的，这些 T 细胞识别所表达的同种异体抗原影响宿主细胞并随后损害宿主正常组织。除了 MHC 刺激的 TCR 信号传导外，抗原复合物、共刺激途径参与 T 细胞的激活和功能。共刺激 CD27 分子是 T 细胞上表达的 TNF 受体家族成员，其配体 CD70 已知在活化的抗原呈递细胞 (APC) 和 T 细胞上表达。先前的研究主要使用病毒感染模型在很大程度上将这一途径描述为“刺激性”，并且是最佳 T 细胞所必需的反应，而其在异基因 HCT 中的作用以前未知。在这个项目中，我们使用了已建立的小鼠研究 CD27/CD70 在 GVHD 中的作用的模型。我们的结果揭示了其发挥的新的抑制作用途径如 2 个方面所指定：1) allo-HCT 显示 CD27-/- 和 CD70-/- 供体 T 细胞引起更多 GVHD 比 WT 供体 T 细胞严重，表明供体 T 细胞中的 CD27/CD70 信号传导抑制同种异体 T细胞反应； 2）当用作allo-HCT宿主时，CD27-/-和CD70-/-小鼠表现出更严重的 GVHD 与 WT 宿主相比，表明宿主中的 CD27/CD70 信号传导抑制同种异体 T 细胞回复。初步机制分析表明，该途径通过限制供体 T 细胞来抑制 GVHD 以不依赖于供体调节性 T 细胞的方式扩增并减少促炎细胞因子。基于根据这些结果，我们的中心假设是 CD27/CD70 信号通过以下方式发挥抑制 GVHD 的新作用：抑制同种异体炎症 T 细胞反应。我们提出了三个目标来系统地追求捐助者 T 细胞衍生机制、宿主衍生机制以及该途径在以下情况下的临床相关性移植物抗宿主病。了解这些机制对于制定能够控制的创新战略至关重要 GVHD 并改善异基因 HCT 患者的生活质量。