Temporal Regulation of Immune Response during GvHD via IL-33/ST2 axis

Similar abstract has been appporved for a conference (OAK22720). IL-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces proinflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory GVHD and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by non-hematopoietic cells in the GI tract in mice postconditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and TNF-α production was significantly reduced in il33-/- recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2-/- versus wildtype donor T cells had a marked reduction in GvHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2-/- T cells, and linked to reduced IFN-γ production by st2-/- versus wildtype T cells during GVHD. Blockade of IL-33/ST2 interactions during allo-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to targeting of the IL-33/ST2 axis as a novel and potent target for GVHD therapy