Abstract
Graft-versus-host disease (GvHD) remains a significant complication of allogeneic hematopoietic cell transplantation (HCT), associated with significant morbidity and mortality. GvHD is characterized by dysregulated immune responses and resulting tissue damage of target organs. Recent investigations have focused on Foxp3+ regulatory T cells (Tregs) as a therapeutic tool, based on its regulatory functions in GvHD pathogenesis and their instrumental role in mitigating GvHD severity while preserving graft-versus-leukemia (GvL) activity. There are several challenges to its clinical application, including their paucity, impaired suppressive activity, and instability in vivo. Herein, we report that IL-27 pre-stimulation enhances suppressive functions of both mouse and human Tregs. In a complete MHC mismatched murine bone marrow transplant model, IL-27 pre-stimulated polyclonal iTregs diminish acute (a)GvHD lethality, while preserving the GvL effect. Allo-antigen specificity further improves suppressive functions when combined with IL-27 pre-stimulation. In a xenogeneic (human to mouse) GvHD model, IL-27 pre-stimulated human iTregs are superior in protecting recipients from GvHD. Lastly, we compared gene expression profiles of circulating Tregs isolated from HCT recipients with and without aGvHD and found that Tregs from aGvHD patients express distinct gene signatures enriched in immune activation and inflammation. Therefore, these results highlight a novel function of IL-27 in enforcing Treg functions to prevent aGvHD mediated lethality, proposing the hypothesis that dysregulated Treg functions may account for the potential mechanisms underlying GvHD development.
Highlights
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for high risk hematologic malignancies, it is frequently complicated by graft-versus-host disease (GvHD), and remains a major cause of transplant-related morbidity and mortality [1,2,3]
We present the evidence that IL-27 pre-stimulation of Tregs at ratios 1:1–1:32 (Treg) effectively enhances their function to suppress systemic inflammation induced during allogeneic HCT and Graft-versus-host disease (GvHD)
Using complete MHC-mismatched aGvHD mouse models, we demonstrate that Tregs, whether thymus-derived or in vitrogenerated, acquire highly suppressive capacity to prevent the development of aGvHD following IL-27 pre-stimulation prior to transfer
Summary
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for high risk hematologic malignancies, it is frequently complicated by graft-versus-host disease (GvHD), and remains a major cause of transplant-related morbidity and mortality [1,2,3]. Regulatory T cells (Tregs) are the central regulators of tolerance and immunity, and can be categorized into thymus-derived Tregs (tTregs), peripheral Tregs (pTregs), IL-27 and in vivo Treg Suppressive Functions and in vitro-generated Tregs (iTregs) based on the mode of generation [4, 5]. Ex vivo protocols to expand tTregs in sufficient numbers for infusion therapies have been developed [9, 10]; antigen-nonspecificity, stability, and cost-effectiveness still remain critical obstacles to overcome [11]. The use of iTregs to suppress inflammatory conditions remains a challenge as they tend to lose Foxp expression and suppressive activity [16,17,18], warranting the need for new approaches to increase their stability and/or suppressive function for clinical use
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