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

Jilu Zhang, Abdulraouf M. Ramadan, Brad Griesenauer, Wei Li, Matthew J. Turner, Chen Liu, Reuben Kapur, Helmut Hanenberg, Bruce R. Blazar, Isao Tawara, Sophie Paczesny

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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-g, 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.

Original languageEnglish (US)
Article number308ra160
JournalScience Translational Medicine
Volume7
Issue number308
DOIs
StatePublished - Oct 7 2015

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Graft vs Host Disease
T-Lymphocytes
Membranes
Interleukin-17
Interleukin-23
Th2 Cells
Immune System Diseases
Cell Transplantation
Regulatory T-Lymphocytes
Stromal Cells
Green Fluorescent Proteins
Neutralizing Antibodies
Acute Myeloid Leukemia
Interleukin-10
Dendritic Cells
Interferons
Leukemia
Biomarkers
Monoclonal Antibodies
Cell Membrane

ASJC Scopus subject areas

  • Medicine(all)

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ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. / Zhang, Jilu; Ramadan, Abdulraouf M.; Griesenauer, Brad; Li, Wei; Turner, Matthew J.; Liu, Chen; Kapur, Reuben; Hanenberg, Helmut; Blazar, Bruce R.; Tawara, Isao; Paczesny, Sophie.

In: Science Translational Medicine, Vol. 7, No. 308, 308ra160, 07.10.2015.

Research output: Contribution to journalArticle

Zhang, Jilu ; Ramadan, Abdulraouf M. ; Griesenauer, Brad ; Li, Wei ; Turner, Matthew J. ; Liu, Chen ; Kapur, Reuben ; Hanenberg, Helmut ; Blazar, Bruce R. ; Tawara, Isao ; Paczesny, Sophie. / ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. In: Science Translational Medicine. 2015 ; Vol. 7, No. 308.
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AU - Li, Wei

AU - Turner, Matthew J.

AU - Liu, Chen

AU - Kapur, Reuben

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