Novel regulatory therapies for prevention of Graft-versus-host disease

Graft-versus-host disease (GVHD) remains a major obstacle for the clinical application of hematopoietic stem cell (HSC) transplantation [1]. GVHD is initiated by alloreactive donor T cells which recognize the host minor and major histocompatibility (MHC) antigens, proliferate, and damage target tissues. Donor T cells have been shown to enhance engraftment of HSC, reconstitute T cell immunity, and mediate a potent beneficial anti-tumor effect, known as graft-versus-leukemia (GVL) effect. Depletion of donor T cells impairs engraftment of HSC and abrogates the T cell-mediated GVL effect. In addition, administration of immunosuppressive drugs to prevent GVHD after HSC transplantation impairs T cell function and increases the risk of opportunistic infection and tumor relapse. Therefore, recent approaches have focused on tailored approaches to maintain the desirable effect of GVL yet avoid GVHD after HSC transplantation. Recent preclinical novel cell-based therapies have been developed to achieve these outcomes. They are currently being translated to the clinic.The mechanisms of donor T cell (CD4+ T cell and CD8+ T cell)-mediated GVHD are multifactorial and include activation of macrophages and antigen-presenting cells (APC) by transplantation conditioning regimens to damage host tissue, releasing soluble cytokines such as TNF-α and IL-1; alloreactive T cell activation, proliferation and differentiation in response to host or donor APC; and alloreactive T cell infiltration and release of pro-inflammatory cytokines which leads to damage of the target tissue [2]. Over the past two decades, the importance of regulatory populations of lymphocytes in controlling immune responses has been increasingly appreciated. Although different cell subsets with regulatory activity have been described, including CD4+/CD25+/forkhead/winged helix transcription factor + (FoxP3+), CD8+/CD28-, T/natural killer (NK) cells, and TCR+/CD4-/CD8-, most studies have concentrated on CD4+/CD25+/FoxP3+ T