Research ArticleGRAFT VERSUS HOST DISEASE

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

Science Translational Medicine  07 Oct 2015:
Vol. 7, Issue 308, pp. 308ra160
DOI: 10.1126/scitranslmed.aab0166

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Blocking graft-versus-host disease

Bone marrow transplantation replaces unhealthy bone marrow with bone marrow from a healthy donor. However, the donor-derived immune cells may recognize the transplant recipient as foreign and attack, resulting in graft-versus-host disease (GVHD). Now, Zhang et al. report that blocking soluble suppression of tumorigenicity 2 (sST2), a plasma marker for GVHD, with a neutralizing antibody can reduce GVHD severity and mortality. The blockade decreased the production of proinflammatory cytokines and increased the frequency of anti-inflammatory molecules and cells while maintaining graft-versus-leukemia activity. These data suggest that targeting sST2 may help decrease GVHD after bone marrow transplantation.

Abstract

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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