Immunomodulatory effects of rapamycin in xenogeneic Graft versus Host Disease

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Several studies have suggested that rapamycin (RAPA), an mTOR inhibitor with immunosuppressive properties, may reduce GVHD severity and mortality, possibly by promoting regulatory T cells (Tregs). However, few data have been reported about the impact of this drug on overall T cell population. The present work aims at investigating the mechanisms by which RAPA impacts GVHD in a humanized mouse model of GVHD (NSG mice infused with human PBMCs). We observed that RAPA injections significantly reduced xenogeneic GVHD lethality and severity. RAPA dramatically reduced human cells chimerism in RAPA mice and increased CD4+/CD8+ T cells balance due to a lower proliferation of CD8+ T cells. In addition, the frequencies of naive CD4+ and CD8+ T cells were higher and the CD4+ T cells showed a reduced effector phenotype (CD45RO+CD27-). Further, the differentiation of helper T cells (Th1, Th2 and Th17) was significantly decreased in treated mice. Tregs were positively affected as RAPA up-regulated their expression of BCL-2 and KI67 as well as their STAT5 phosphorylation level, leading to higher Treg frequency in treated mice. Altogether these data suggest that RAPA ameliorates GVHD by lowering cytotoxic and effector CD4+ T cells frequency as well as promoting Tregs.