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Front Immunol. 2017 Jun 8;8:667. doi: 10.3389/fimmu.2017.00667. eCollection 2017.

Interleukin-6 in Allogeneic Stem Cell Transplantation: Its Possible Importance for Immunoregulation and As a Therapeutic Target.

Author information

1
Department of Clinical Science, Section for Hematology, University of Bergen, Bergen, Norway.
2
Department of Medicine, Haukeland University Hospital, Bergen, Norway.
3
Institute of Biomedical Laboratory Sciences and Chemical Engineering, Western Norway University of Applied Sciences (HVL), Bergen, Norway.
4
Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway.

Abstract

Allogeneic stem cell transplantation is associated with a high risk of treatment-related mortality mainly caused by infections and graft-versus-host disease (GVHD). GVHD is characterized by severe immune dysregulation and impaired regeneration of different tissues, i.e., epithelial barriers and the liver. The balance between pro- and anti-inflammatory cytokine influences the risk of GVHD. Interleukin-6 (IL-6) is a cytokine that previously has been associated with pro-inflammatory effects. However, more recent evidence from various autoimmune diseases (e.g., inflammatory bowel disease, rheumatoid arthritis) has shown that the IL-6 activity is more complex with important effects also on tissue homeostasis, regeneration, and metabolism. This review summarizes the current understanding of how pro-inflammatory IL-6 effects exerted during the peritransplant period shapes T-cell polarization with enhancement of Th17 differentiation and suppression of regulatory T cells, and in addition we also review and discuss the results from trials exploring non-selective IL-6 inhibition in prophylaxis and treatment of GVHD. Emerging evidence suggests that the molecular strategy for targeting of IL-6-initiated intracellular signaling is important for the effect on GVHD. It will therefore be important to further characterize the role of IL-6 in the pathogenesis of GVHD to clarify whether combined IL-6 inhibition of both trans- (i.e., binding of the soluble IL-6/IL-6 receptor complex to cell surface gp130) and cis-signaling (i.e., IL-6 ligation of the IL-6 receptor/gp130 complex) or selective inhibition of trans-signaling should be tried in the prophylaxis and/or treatment of GVHD in allotransplant patients.

KEYWORDS:

Janus kinases; allogeneic stem cell transplantation; cytokine receptor gp130; graft-versus-host disease; interleukin-6

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