Pharmacologic expansion of donor-derived, naturally occurring CD4(+)Foxp3(+) regulatory T cells reduces acute graft-versus-host disease lethality without abrogating the graft-versus-leukemia effect in murine models.

摘要

Adoptive transfer of regulatory T cells (Tregs) prevents graft-versus-host disease (GVHD) in mouse models, indicating a pivotal role for Tregs in controlling GVHD. The present study demonstrates the efficacy of Tregs pharmacologically induced in vivo in GVHD prevention. A single i.v. administration of a liposomal formulation of alpha-galactosylceramide (RGI-2001) at the time of allogeneic bone marrow transplantation with spleen cells significantly prolonged the survival of mice experiencing lethal acute GVHD. RGI-2001 expanded donor-derived CD4(+)Foxp3(+) Tregs in the spleen, lymph nodes, and bone marrow in a dose-dependent manner. On day 15 posttransplantation, the spleens of mice treated with RGI-2001 (1 mug/kg) contained 5-fold higher percentages or 10-fold higher numbers of CD4(+)Foxp3(+) Tregs compared with the spleens of untreated mice. Host-specific immunosuppression was introduced in treated mice, whereas the responsiveness to third-party alloantigens and leukemia cells was maintained. Using Foxp3:GFP reporter mice as donors, it was clearly shown that RGI-2001 expanded the pre-existing naturally occurring Tregs (nTregs) in donor spleen cells. Finally, RGI-2001 synergized with a subtherapeutic dose of rapamycin in nTreg expansion and further prolonged survival. Our results provide the first demonstration of the efficacy of nTregs pharmacologically expanded in vivo in preventing acute GVHD without abrogation of the beneficial graft-versus-leukemia effect.