ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease

J Zhang, AM Ramadan, B Griesenauer, W Li… - Science translational …, 2015 - science.org
J Zhang, AM Ramadan, B Griesenauer, W Li, MJ Turner, C Liu, R Kapur, H Hanenberg
Science translational medicine, 2015science.org
Graft-versus-host disease (GVHD) remains a devastating complication after allogeneic
hematopoietic cell transplantation (HCT). We previously identified high plasma soluble
suppression of tumorigenicity 2 (sST2) as a biomarker of the development of GVHD and
death. sST2 sequesters interleukin-33 (IL-33), limiting its availability to T cells expressing
membrane-bound ST2 (mST2)[T helper 2 (TH2) cells and ST2+ FoxP3+ regulatory T cells].
We report that blockade of sST2 in the peritransplant period with a neutralizing monoclonal …
Graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We previously identified high plasma soluble suppression of tumorigenicity 2 (sST2) as a biomarker of the development of GVHD and death. sST2 sequesters interleukin-33 (IL-33), limiting its availability to T cells expressing membrane-bound ST2 (mST2) [T helper 2 (TH2) cells and ST2+FoxP3+ regulatory T cells]. We report that blockade of sST2 in the peritransplant period with a neutralizing monoclonal antibody (anti-ST2 mAb) reduced GVHD severity and mortality. We identified intestinal stromal cells and T cells as major sources of sST2 during GVHD. ST2 blockade decreased systemic interferon-γ, IL-17, and IL-23 but increased IL-10 and IL-33 plasma levels. ST2 blockade also reduced sST2 production by IL-17–producing T cells while maintaining protective mST2-expressing T cells, increasing the frequency of intestinal myeloid–derived suppressor cells, and decreasing the frequency of intestinal CD103 dendritic cells. Finally, ST2 blockade preserved graft-versus-leukemia activity in a model of green fluorescent protein (GFP)–positive MLL-AF9 acute myeloid leukemia. Our findings suggest that ST2 is a therapeutic target for severe GVHD and that the ST2/IL-33 pathway could be investigated in other T cell–mediated immune disorders with loss of tolerance.
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