在 mTOR 阻断作用下,通过接近内皮细胞对 T 细胞介导的异体免疫进行免疫调节。

IF 8.9 2区 医学 Q1 SURGERY American Journal of Transplantation Pub Date : 2024-10-17 DOI:10.1016/j.ajt.2024.10.008
Shu Li,Liuyang Wang,Victoria A Bendersky,Qimeng Gao,Jun Wang,He Xu,Allan D Kirk
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引用次数: 0

摘要

内皮细胞(EC)是血管化器官同种异体移植物与宿主免疫系统之间的初始屏障,因此能很好地启动和影响同种异体免疫排斥反应。众所周知,mTOR抑制剂雷帕霉素能抑制T细胞活化,减轻急性同种异体移植排斥反应(AR)。它对EC也有许多影响。我们推测,mTOR阻断剂可能会直接改变EC的异体免疫原性并减少异体免疫反应,而不依赖于其对T细胞功能的影响。在这里,我们报告了雷帕霉素治疗可调节EC共抑制配体的表达并改变细胞因子/趋化因子的产生。雷帕霉素改变了与免疫反应负调控广泛相关的EC转录组。雷帕霉素处理的EC会抑制EC特异性T细胞的增殖,而不依赖于PD1/PD配体的相互作用,并通过分泌10 kDa以上的抑制介质,以不依赖于接触的方式抑制T细胞对邻近的异体细胞产生反应。经雷帕霉素预处理的EC诱导的T细胞低反应性可被外源IL-2所挽救。在MHC不匹配的小鼠模型中,供体心脏预先暴露于雷帕霉素可改善B7成本刺激阻断在延长心脏异体移植存活率方面的效果。我们的研究结果表明,雷帕霉素处理过的心肌降低了异体免疫原性,并创造了一个不依赖接触的局部环境,通过诱导过敏限制了T细胞异体活性,提高了B7成本刺激阻断的效果。
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Immunomodulation of T cell-mediated Alloimmunity by Proximity to Endothelial Cells under mTOR Blockade.
Endothelial cells (ECs) are an initial barrier between vascularized organ allografts and the host immune system and are thus well positioned to initiate and influence alloimmune rejection. The mTOR inhibitor rapamycin is known to inhibit T cell activation and attenuate acute allograft rejection (AR). It also has numerous effects on ECs. We hypothesized that mTOR blockade might directly alter EC alloimmunogenicity and reduce alloimmune responses independent of its effects on T cell function. Here we report that rapamycin treatment modulates EC coinhibitory ligand expression and alters cytokine/chemokine production. It alters the EC transcriptome broadly associated with negative regulation of immune responses. Rapamycin-treated ECs suppress EC-specific T cell proliferation independent of PD1/PD ligand interactions, and inhibit T cells responding to adjacent allogeneic cells in a contact-independent manner via secreted inhibitory mediators above 10 kDa. The T cell hypo-responsiveness induced by rapamycin-pretreated ECs was rescued by exogenous IL-2. Pre-exposing donor hearts to rapamycin improves the effect of B7 costimulation blockade in prolonging heart allograft survival in an MHC-mismatched mouse model. Our results indicate that rapamycin treated ECs have reduced alloimmunogenicity and create a local, contact-independent environment that limits T cell alloreactivity via anergy induction and improves the efficacy of B7 costimulation blockade.
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来源期刊
CiteScore
18.70
自引率
4.50%
发文量
346
审稿时长
26 days
期刊介绍: The American Journal of Transplantation is a leading journal in the field of transplantation. It serves as a forum for debate and reassessment, an agent of change, and a major platform for promoting understanding, improving results, and advancing science. Published monthly, it provides an essential resource for researchers and clinicians worldwide. The journal publishes original articles, case reports, invited reviews, letters to the editor, critical reviews, news features, consensus documents, and guidelines over 12 issues a year. It covers all major subject areas in transplantation, including thoracic (heart, lung), abdominal (kidney, liver, pancreas, islets), tissue and stem cell transplantation, organ and tissue donation and preservation, tissue injury, repair, inflammation, and aging, histocompatibility, drugs and pharmacology, graft survival, and prevention of graft dysfunction and failure. It also explores ethical and social issues in the field.
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