Targeted gastrointestinal tract homing of regulatory T-cells reduces acute graft-versus-host disease severity by simulating an increase in Treg dose in vivo

Abstract Damage to the gastrointestinal (GI) tract following hematopoietic stem cell transplant (HSCT) has been shown to drive the development of acute graft-versus-host disease (aGVHD). We have demonstrated clinically that infusing regulatory T-cells (Treg) during HSCT reduces aGVHD risk while supporting immune recovery; however, high Treg doses were necessary. Here we demonstrate that by promoting Treg homing to the GI tract early post-HSCT, aGVHD severity was reduced. Ex vivo expanded murine Treg were retrovirally transduced to overexpress the orphan chemoattractant receptor GPR15 for colon specific T-cell homing. Despite no change in Treg phenotype or in vitro suppressive function when administered to HSCT recipient mice at the time of transplantation, mice that received GPR15+ Treg exhibited significantly reduced aGVHD severity and prolonged survival compared to control Treg mice (p = 0.0035). To confirm that this resulted from an increased Treg accumulation in the GI tissues, we then assessed the frequency and retention of GPR15+ Treg in mice post-HSCT by in vivo and ex vivo bioluminescent imaging as well as flow analysis. From these data, we observed not only superior localization of GPR15+ Treg within GI tissues, but also significantly reduced inflammation and tissue damage in GPR15+ Treg recipient mice early post-HSCT. Our data provides evidence that deliberate targeting of ex vivo expanded Treg to the GI tract during HSCT significantly reduces injury to the GI tract and reduces aGVHD severity by simulating an increase in Treg dose in vivo. These data provide a rational for the future development of clinical Treg products for increased control of GI aGVHD following HSCT.