Reichenbach, Dawn K., Schwarze, Vincent, Matta, Benjamin M., Tkachev, Victor, Lieberknecht, Elisabeth, Liu, Quan, Koehn, Brent H., Pfeiffer, Dietmar, Taylor, Patricia, Prinz, Gabriele, Dierbach, Heide, Stickel, Natalie, Yvonne, Beck, Warncke, Max, Junt, Tobias, Schmitt-Graeff, Anette, Nakae, Susumu, Follo, Marie, Wertheimer, Tobias, Schwab , Lukas, Devlin, Jason, Watkins, Simon C., Duyster, Justus, Ferrara, James L.M., Turnquist, Heth R., Zeiser, Robert and Blazar, Bruce R. (2015) Temporal Regulation of Immune Response during GvHD via IL-33/ST2 axis. Blood.

Abstract

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.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25335