Regulatory T-Cell Therapy for Graft-versus-host Disease

Abstract

Graft-versus-host disease (GVHD) is a significant cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Existing strategies to prevent and treat GVHD are incomplete, where a significant portion of allo-HCT recipients developed this complication. Despite this, one such therapy has emerged involving the use of regulatory T cells (Tregs) to control GVHD. The use of natural Tregs (nTregs) yielded positive pre-clinical results and are actively under investigation to reduce GVHD. However, broad application of this approach may require standardization of Treg expansion methods and dosing. Inducible Tregs (iTregs) can be seamlessly generated, but controversial pre-clinical findings and phenotype instability have hampered their translation into the clinic. Here, we review the current biological differences between nTregs and iTregs, as well as their effects on GVHD and graft-versus-leukemia (GVL) responses. We conclude by exploring the idea of combinational cellular therapies for the prevention of GVHD and preservation of GVL.

Keywords: Cellular therapy; Graft-versus-host disease (GVHD); iTregs; nTregs.

Figure 1. Delicate Balance between GVH and GVL responses

Following allogeneic HSCT, effector T cells within the graft inoculum recognize non-hematopoietic and hematopoietic allo-antigens presented by host and/or donor APCs resulting in both graft-versus-host (GVH) and graft-versus-leukemia (GVL) responses. Treg therapy could improve outcomes in allo-HSCT by greatly inhibiting Teffs cells causing GVHD with little or partial inhibition of the GVL effect.

Figure 2. Comparison of nTregs and iTregs: Generation, Suppressive Mechanism, and Stability

For generation nTregs and iTregs are distinct, with nTregs requiring recognition of self-antigen, costimulation, and IL-2; whereas iTregs recognize foreign antigen and require IL-2, TGFβ, and RA. nTregs and iTregs share suppressive mechanisms, broadly defined as direct cytolysis, suppressive cytokines, metabolic disruption, IL-2 deprivation, and contact dependent suppression. nTregs are more stable than iTregs with a fully demethylated CNS2 region with the foxp3 gene whereas iTregs sometimes display a partially methylated CNS2.