Tregs in Allogeneic Hematopoietic Stem Cell Transplantation: Suppressing Graft-Versus-Host Disease while Preserving Graft-Versus-Leukemia

Abstract

Graft-versus-host disease (GVHD) is still a significant challenge for allogeneic hematopoietic stem cell transplantation, resulting in substantial non-relapse mortality. Regulatory T cells (Tregs) are essential for modulating immune responses and maintaining tolerance, resulting in a promising therapeutic approach for GVHD management. The purpose of this study is to explore the immunomodulatory effect of Tregs in preventing and managing GVHD without sacrificing the graft-versus-leukemia (GVL) effect. Preclinical and clinical studies demonstrate that ex vivo-expanded Tregs, derived from donor peripheral blood or umbilical cord blood, effectively reduce GVHD incidence when infused prophylactically. Combination therapies, including Tregs with tacrolimus or invariant natural killer T cell activation via a-galactosylceramide, enhance Treg's efficacy and reduce required cell doses. Improved Treg stability and in vivo expansion can be achieved through advanced strategies such as rapamycin-assisted expansion and orthogonal inter-leukin-2 (IL-2)/IL-2Rb systems. These findings highlight Tregs' potential to mitigate GVHD without compromising GVL, offering a biologically favorable alternative to traditional immunosuppression. Further randomized trials are needed to standardize protocols and confirm long-term efficacy in the face of challenges in Treg isolation, expansion, optimal dosing, and infusion timing, which will lead to improved transplant outcomes. (c) 2026 American Society for Transplantation and Cellular Therapy. Published by Elsevier, Inc.