Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft-versus-host disease prophylaxis
Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft-versus-host disease prophylaxis
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DOI：
10.1111/ajt.16505
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发表时间：
2021-02-19
影响因子：
8.8
通讯作者：
Baron, Frederic
中科院分区：
文献类型：
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作者：
Ehx, Gregory;Ritacco, Caroline;Baron, Frederic
移植物抗宿主病（GVHD）是异基因造血细胞移植（allo-HCT）后毒性的主要原因。虽然雷帕霉素（RAPA）通常与钙调磷酸酶抑制剂（CNI）组合用于GVHD预防，但对其对人T细胞的作用机制的理解仍然不完全。在这里，我们进行了广泛的分析RAPA对人类T细胞的作用，在人源化小鼠模型的GVHD，在离体T细胞培养和患者给予RAPA加他克莫司作为GVHD预防后，非清髓性allo-HCT。我们证明RAPA通过减少T细胞植入和分化、抑制CD 8（+）T细胞活化和增加长期IL-2分泌来减轻GVHD，从而支持调节性T细胞（Treg）增殖。相比之下，移植物抗白血病效应没有被消除，因为RAPA处理的T细胞对凋亡的抗性增加，并且在再刺激时保留了它们的效应子功能和增殖能力。重要的是，我们发现RAPA对Treg和CD 8（+）T细胞的影响密切依赖于IL-2信号传导，并且干扰IL-2的治疗选择，如钙调磷酸酶抑制剂，拮抗RAPA介导的Treg的IL-2依赖性促进。我们的研究结果表明，RAPA的免疫效力可以提高与药物组合具有可能的协同作用，如低甲基化剂5-氮杂胞苷。
Graft-versus-host disease (GVHD) is a major cause of toxicity after allogeneic hematopoietic cell transplantation (allo-HCT). While rapamycin (RAPA) is commonly used in GVHD prophylaxis in combination with a calcineurin inhibitor (CNI), the understanding of its mechanism of action on human T cells is still incomplete. Here, we performed an extensive analysis of RAPA effects on human T cells in a humanized mouse model of GVHD, in ex-vivo T cell cultures and in patients given RAPA plus tacrolimus as GVHD prophylaxis after nonmyeloablative allo-HCT. We demonstrate that RAPA mitigates GVHD by decreasing T cell engraftment and differentiation, inhibiting CD8(+) T cell activation and increasing the long-term IL-2 secretion, thereby supporting regulatory T cell (Treg) proliferation. In contrast, graft-versus-leukemia effects were not abrogated, as RAPA-treated T cells had increased resistance to apoptosis and retained their effector function and proliferative capacity upon re-stimulation. Importantly, we found that RAPA impact on Treg and CD8(+) T cells was closely dependent upon IL-2 signaling and that therapeutic options interfering with IL-2, such as calcineurin inhibitors, antagonize the IL-2-dependent promotion of Treg mediated by RAPA. Our results suggest that RAPA immunological efficacy could be improved in combination with drugs having possible synergistic effects such as the hypomethylating agent 5-azacytidine.