DRAK2 is a promising target to inhibit GvHD without negatively impacting graft reconstitution after bone marrow transplant

Abstract

Abstract Graft versus host disease (GvHD) is the most common adverse event after allogeneic bone marrow transplant (BMT). GvHD and the immunosuppression required to treat it limit the desired graft versus leukemic effect and are associated with significant morbidity and mortality. A treatment that selectively controls the harmful immune response during GvHD, without compromising the response to pathogens or tumors, would be transformative. Previously, we demonstrated that mice deficient in Drak2 (Drak2−/−) are resistant to disease in multiple models of T cell-mediated autoimmunity but maintain effective responses to pathogens and tumors. Since similar immune pathologies mediate GvHD and autoimmunity, we sought to investigate whether loss of Drak2 reduced GvHD, while maintaining effective immunity to pathogens. Thus, we utilized a murine model of acute GvHD (aGvHD) in which lethally irradiated mice received MHC-mismatched bone marrow and purified T cells that were either Drak2+/+ or Drak2−/−. We found that mice given MHC-mismatched bone marrow along with Drak2−/− T cells had less severe aGvHD compared to mice receiving Drak2+/+ T cells, as demonstrated by lower clinical scores. Interestingly, mice given Drak2−/− T cells along with MHC-mismatched bone marrow had increased proportions of regulatory T cells and decreased effector T cells compared to mice given wildtype T cells. These data suggest that Drak2 expression within T cells contributes to GvHD development, and therefore is a promising target in the treatment of GvHD. Ongoing studies are investigating whether the absence of Drak2 influences the effective repopulation of a functional immune system following BMT. Funding provided by ALSAC and the St. Jude Graduate School of Biomedial Sciences