常用移植后免疫抑制剂的体外分析揭示了它们对 CMV 抗病毒 T 细胞免疫的不同影响

Markus Benedikt Krueger, Agnes Bonifacius, A. Dragon, Maria Michela Santamorena, Björn Nashan, Richard Taubert, Ulrich Kalinke, B. Maecker-Kolhoff, Rainer Blasczyk, B. Eiz-Vesper
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引用次数: 0

摘要

造血干细胞和实体器官移植后,由于免疫抑制治疗导致T细胞免疫功能受损,经常会出现感染并发症,包括广泛的人类巨细胞病毒(CMV)疾病。因此,需要深入分析免疫抑制剂对抗病毒 T 细胞的影响。我们分析了 mTOR 抑制剂西罗莫司(SIR/S)和依维莫司(EVR/E)、钙神经蛋白抑制剂他克莫司(TAC/T)、嘌呤合成抑制剂霉酚酸(MPA/M)、糖皮质激素泼尼松龙(PRE/P)以及常见的双联(T+S/E/M/P)和三联(T+S/E/M+P)对抗病毒 T 细胞功能的影响。T细胞在抗原刺激下的活化和效应分子的产生在T+P和三重组合的作用下受到损害。SIR、EVR 和 MPA 只抑制 T 细胞增殖,TAC 抑制活化和细胞因子的产生,而 PRE 则抑制 T 细胞功能的各个方面,包括细胞毒性。这反映在体外感染模型中,CMV 特异性 T 细胞对受 CMV 感染的人成纤维细胞的清除率在 PRE 和所有三重组合存在时均有所降低。TAC和PRE抑制了CMV特异性记忆T细胞,这也反映在双重(T+P)和三重组合中。EBV和SARS-CoV-2特异性T细胞也受到类似影响。这些结果凸显了优化免疫监测的必要性,以确定哪些患者可能从个体化的免疫抑制中获益。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In Vitro Profiling of Commonly Used Post-transplant Immunosuppressants Reveals Distinct Impact on Antiviral T-cell Immunity Towards CMV
Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to immunosuppressive treatment causing impairment of T-cell immunity. Therefore, in-depth analysis of the impact of immunosuppressants on antiviral T cells is needed. We analyzed the impact of mTOR inhibitors sirolimus (SIR/S) and everolimus (EVR/E), calcineurin inhibitor tacrolimus (TAC/T), purine synthesis inhibitor mycophenolic acid (MPA/M), glucocorticoid prednisolone (PRE/P) and common double (T+S/E/M/P) and triple (T+S/E/M+P) combinations on antiviral T-cell functionality. T-cell activation and effector molecule production upon antigenic stimulation was impaired in presence of T+P and triple combinations. SIR, EVR and MPA exclusively inhibited T-cell proliferation, TAC inhibited activation and cytokine production and PRE inhibited various aspects of T-cell functionality including cytotoxicity. This was reflected in an in vitro infection model, where elimination of CMV-infected human fibroblasts by CMV-specific T cells was reduced in presence of PRE and all triple combinations. CMV-specific memory T cells were inhibited by TAC and PRE, which was also reflected with double (T+P) and triple combinations. EBV- and SARS-CoV-2-specific T cells were similarly affected. These results highlight the need to optimize immune monitoring to identify patients who may benefit from individually tailored immunosuppression.
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