期刊
BLOOD
卷 125, 期 20, 页码 3183-3192出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-10-606830
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资金
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01 AI34495]
- National Heart, Lung, and Blood Institute [R01 HL56067, T32 HL007062]
- Deutsche Forschungsgemeinschaft, Germany [SFB620]
- Heisenberg Professorship [DFG ZE 872/3-1]
- DFG Einzelantrag [ZE 872/1-2]
- National Institutes of Health, National Heart, Lung, and Blood Institute [R00 HL097155]
- National Institute of Allergy and Infectious Diseases [T32AI074490]
- American Society of Transplantation/Pfizer Basic Science Faculty Development Grant
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(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) 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(-/-) T cells, and linked to reduced interferon-g production by st2(-/-) 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.
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