Impact des cellules souches mésenchymateuses et de la rapamycine sur la maladie du greffon contre l'hôte xénogénique

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation caused by donor T cells reacting against host tissues. Previous studies have suggested that mesenchymal stromal cells (MSC) could exert potent immunosuppressive effects.In first time, the aim of our study was to develop xenogeneic GVHD in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice and in NOD/SCID/interleukin-2Rgamma;null (NSG) mice transplanted with human peripheral blood mononuclear cells (PBMC). Secondly, we assessed human bone marrow derived MSC to prevent xenogeneic GVHD in these mouse models.We observed that injection of 200 × 106 human PBMC intraperitoneally (IP) into sub-lethally (3.0 Gy) irradiated NOD/SCID mice also given anti-asialo GM1 antibodies IP 1 day prior and 8 days after transplantation induced lethal xenogeneic GVHD in all tested mice. Co-injection of 2 × 106 MSC IP on day 0 did not prevent lethal xenogeneic GVHD induced by injection of human PBMC. Similarly, injection of 30 × 106 human PBMC IP into sub-lethally (2.5 Gy) irradiated NSG mice induced a lethal xenogeneic GVHD in all tested mice. Injection of 3 × 106 MSC IP on days 0, 7, 14 and 21 did not prevent lethal xenogeneic GVHD induced by injection of human PBMC.The administration of RAPA (or sirolimus) is one of the other therapeutic strategies considered in the context of the prevention of GVHDa. Rapamycin (Sirolimus; RAPA) is an inhibitor of the mammalian target of rapamycin (mTor) which can induce tolerance by inhibiting activated T cells without diminishing CD4+CD25+Foxp3+ regulatory T cells Treg) proliferation and suppressive function. In second time, the aim of the current study was to assess the impact of RAPA administration on xenogeneic graft-versus-host disease (xGVHD) in NSG mice.NSG mice were given 2.5 Gy total body irradiation on day-1 and an intravenously (i.v.) injection of 2 × 106 human peripheral blood mononuclear cells (PBMC) on day 0. RAPA was administered intraperitoneally (i.p.) five days/week at a dose of 1.5 mg/kg from day -1 to day 14, and at 1 mg/kg from day 15 to day 21.We observed that RAPA administration was associated with a lower proportion of conventional T cell in cell cycle on day 20 after transplantation and a reduction in xGVHD lethality. The beneficial impact of RAPA on survival was significantly decreased when CD25-depleted PBMC were transplanted instead of unmanipulated PBMC, suggesting that the beneficial effect of RAPA was mediated at least in part by Treg. However, RAPA did not induce long-term tolerance since RAPA treated mice that survived beyond day 60 developed signs of chronic GVHD.