Premium
Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft‐versus‐host disease prophylaxis
Author(s) -
Ehx Grégory,
Ritacco Caroline,
Han Muriel,
Dubois Sophie,
Delens Loic,
Willems Evelyne,
Servais Sophie,
Drion Pierre,
Beguin Yves,
Baron Frédéric
Publication year - 2021
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.16505
Subject(s) - calcineurin , graft versus host disease , cd8 , immunology , medicine , t cell , sirolimus , transplantation , cancer research , immune system
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.