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:
- 金额:$ 58.61万
- 依托单位:
- 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:
- 关键词:AffectAllogenicAntibodiesAntigen-Presenting CellsAntigensCell surfaceCellsChimera organismComplexComplicationExhibitsFamily memberHematological DiseaseHematopoieticHumanITGAX geneImmune System DiseasesIn VitroIncidenceInfectionInflammatoryLeadLigandsLymphocyteMHC antigenMediatingMemoryMetabolismModelingMorbidity - disease rateMusNormal tissue morphologyOrganPathway interactionsPatientsPlayQuality of lifeRegulationRegulatory T-LymphocyteResistanceRoleSeveritiesSignal TransductionSignal Transduction PathwaySpecific qualifier valueT cell responseT-Cell ActivationT-LymphocyteTNFRSF1A geneTestingTherapeutic immunosuppressionUp-RegulationVirus DiseasesXenograft procedurebaseclinically relevantcurative treatmentscytokinecytotoxicdesignexhaustiongraft vs host diseasehematopoietic cell transplantationimprovedin vivoinnovationmigrationmortalitymouse modelnovelnovel strategiesoverexpressiontherapeutic 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。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Targeting the CD27-CD70 Pathway to Improve Outcomes in Both Checkpoint Immunotherapy and Allogeneic Hematopoietic Cell Transplantation.
- DOI:10.3389/fimmu.2021.715909
- 发表时间:2021
- 期刊:
- 影响因子:7.3
- 作者:Lutfi F;Wu L;Sunshine S;Cao X
- 通讯作者:Cao X
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Xuefang Cao其他文献
Xuefang Cao的其他文献
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{{ truncateString('Xuefang Cao', 18)}}的其他基金
Beta-2 adrenergic signaling in immune homeostasis and reconstitution
免疫稳态和重建中的 Beta-2 肾上腺素能信号传导
- 批准号:
10610471 - 财政年份:2022
- 资助金额:
$ 58.61万 - 项目类别:
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
- 批准号:
9523419 - 财政年份:2018
- 资助金额:
$ 58.61万 - 项目类别:
Targeting Granzyme B to Separate GVH from GVL Responses
靶向颗粒酶 B 将 GVH 与 GVL 反应分开
- 批准号:
9614558 - 财政年份:2017
- 资助金额:
$ 58.61万 - 项目类别:
Targeting Granzyme B to Separate GVH from GVL Responses
靶向颗粒酶 B 将 GVH 与 GVL 反应分开
- 批准号:
9764283 - 财政年份:2017
- 资助金额:
$ 58.61万 - 项目类别:
Targeting Beta-Adrenergic Signaling to Control GVH and GVL Responses
靶向 β-肾上腺素能信号传导来控制 GVH 和 GVL 反应
- 批准号:
9178850 - 财政年份:2016
- 资助金额:
$ 58.61万 - 项目类别:
Targeting Beta-Adrenergic Signaling to Control GVH and GVL Responses
靶向 β-肾上腺素能信号传导来控制 GVH 和 GVL 反应
- 批准号:
9315583 - 财政年份:2016
- 资助金额:
$ 58.61万 - 项目类别:
Targeting Granzyme B to Separate GVH from GVL Responses
靶向颗粒酶 B 将 GVH 与 GVL 反应分开
- 批准号:
8888555 - 财政年份:2015
- 资助金额:
$ 58.61万 - 项目类别:
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