The IL-33/ST2 axis augments effector T-cell responses during acute GVHD

Abstract

Key Points• IL-33 and ST2 expression are increased post-conditioning and with GVHD, resulting in increased T-cell activation via the IL-33/ST2 axis.• Infusion of ST2-Fc protein exploits sST2's function as a negative regulator of acute GVHD inhibiting proinflammatory cytokines.Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (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 nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-a production was significantly reduced in il33 2/2 recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2 2/2 vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2 2/2 T cells, and linked to reduced interferon-g production by st2 2/2 vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-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 the IL-33/ST2 axis as a novel and potent target for GVHD therapy. (Blood. 2015;125(20):3183-3192)

Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells

“…19 HSC are pericytes found in the perisinusoidal space of the liver, and they are the principle source of ECM and collagen. 20,21 Abundant collagen production following liver damage and repair is the hallmark of liver fibrosis and cirrhosis, which may lead to portal hypertension and hepatic failure. 22 HSCs are quiescent at steady state, but on injury, HSCs are activated and produce ECM proteins.…”

“…22 HSCs are quiescent at steady state, but on injury, HSCs are activated and produce ECM proteins. 21 Interleukin-33 (IL-33), a newly described member of the IL-1 family, is expressed by many cell types following proinflammatory stimulation and is released following cell necrosis. 23,24 On binding to ST2 and IL-1 receptor accessory protein to form a trimeric complex, IL-33 activates T helper 2 (Th2) cell differentiation.…”

Prospects to translate the biology of IL-33 and ST2 during organ transplantation into therapeutics to treat graft-versus-host disease

“…Demonstration of a bell shaped dose response would have been strong rationale to support the author's hypothesis. Therefore, given the findings of other studies (12) it seems plausible to suggest that the reduced severity of GVHD in this study may be due to blockade of both mST2 and sST2. Perhaps the strongest evidence to support this hypothesis is that when similar models of GVHD were performed in ST2 knockout mice, lacking both mST2 and sST2, the disease is attenuated (11).…”

“…Furthermore, when exogenous IL-33 is added following allo-HCT, GVHD is exacerbated and mortality is increased. This study suggests that IL-33/ST2 signalling plays a pathogenic role and that neutralisation of IL-33 by sST2 is protective (12).…”

“…Studies in which the IL-33/ST2 axis has been blocked through administration of sST2-Fc show decreased GVHD development and reduced mortality (12). Furthermore, when exogenous IL-33 is added following allo-HCT, GVHD is exacerbated and mortality is increased.…”