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：
9523419
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9523419
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.

同种异体造血细胞透明度（Allo-HCT）是A 然而，血液学和免疫疾病。尽管当前实行的免疫疗法疗法。在宿主细胞上，随后损坏了宿主的正常组织。抗原复合物，共刺激途径在T细胞激活和功能中分子CD27是在T细胞上表达的TNF受体家族，其配体CD70已知为在活化的抗原呈递细胞（APC）和T细胞上表达。感染模型将这种途径刻有“刺激”，并且需要最佳的t -cell 响应，虽然其在Allo-HCTT中的作用在此项目中是未知的。研究CD27/CD70在GVHD中的作用的模型。如两个方面所指定的途径：1）Allo-HCT显示CD27 - / - 和CD70 - / - 供体T细胞都导致更多严重的GVHD比WT供体T细胞，表明供体T细胞中的CD27/CD70信号抑制同种异体 T细胞响应； 2）用作Allo-HCT的宿主时，两只CD27 - / - GVHD与WT宿主相比，表明宿主中的CD27/CD70信号抑制同种异体T细胞反应。基于供体调节性T细胞的方式膨胀和减少促炎性细胞因子。这些esults，我们的中心假设是CD27/CD70信号传导效果没有新颖的支持GVHD 抑制同种异体炎症T细胞反应。细胞衍生的机制，宿主衍生的机制和该途径的临床相关性 GVHD了解此类机制对于制定可以控制的创新策略至关重要 GVHD并改善Allo-HCT患者的生活质量。