[en] 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 non-myeloablative 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.
WILLEMS, Evelyne ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
SERVAIS, Sophie ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
Drion, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Méth. expér. des anim. de labo et éthique en expér. anim.
BEGUIN, Yves ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
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