IL-33 mediated expansion of host ST2(+) T-reg prior to allogeneic hematopoietic cell transplantation decreases macrophage and effector T cell activation reducing acute GVHD

Abstract Graft-versus-host disease (GVHD) is the leading complication and cause of mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Recently, we reported that IL-33 released from tissue damaged during allo-HCT conditioning mediates pro-inflammatory responses by Teffector cells resulting in greater acute GVHD lethality and clinical symptoms in mice. However, IL-33 is a pleiotropic cytokine that mediates both pro-inflammatory and anti-inflammatory responses. We hypothesized that the beneficial effects mediated by IL-33 could be harnessed if IL-33 was present prior to inflammatory mediators released during conditioning. Here, we demonstrate that exogenous IL-33 given peri allo-HCT (days −10 to 4) to recipients of MHC-disparate allo-HCT asserts its immunoregulatory properties reduced GVHD lethality and clinical symptoms compared to non-treated controls. IL-33 treatment peri allo-HCT resulted in the expansion of recipient Treg and suppressive myeloid cells that persisted post irradiation. Host Treg depletion in C57Bl/6 FoxP3-DTR mice by diphtheria toxin given concurrently with peri allo-HCT IL-33 treatment accelerated GVHD symptoms and lethality compared to peri allo-HCT IL-33 treatment alone, demonstrating that host Treg were necessary for GVHD protection. Transfer of Treg deficient in ST2, the IL-33 receptor, afforded less GVHD protection than wild-type Treg. ST2+ Treg controlled macrophage activation and prevented accumulation of Teffector cells in GVHD target tissue. Thus, we demonstrate that peri allo-HCT IL-33 expanded and activated host Treg have potential as a therapeutic modality to prevent and treat GVHD.