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Leukemia. 2018 Nov;32(11):2483-2494. doi: 10.1038/s41375-018-0123-z. Epub 2018 Apr 2.

Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease.

Author information

1
Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA. jchoi25@wustl.edu.
2
Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
3
Department of Medicine, Division of Dermatology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
4
Department of Radiology, Molecular Imaging Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.
5
Department of Microbiology, Kindai University Faculty of Medicine, Osakasayama, Osaka, 589-8511, Japan.
6
Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA. jdipersi@wustl.edu.

Abstract

The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are derived from the graft-versus-leukemia (GvL) effects of the procedure. There is a strong association between the GvL effects and graft-versus-host disease (GvHD), a major life-threatening complication of allo-HSCT. The limiting of GvHD while maintaining the GvL effect remains the goal of allo-HSCT. Therefore, identifying optimal therapeutic targets to selectively suppress GvHD while maintaining the GvL effects represents a significant unmet medical need. We demonstrate that the dual inhibition of interferon gamma receptor (IFNγR) and interleukin-6 receptor (IL6R) results in near-complete elimination of GvHD in a fully major histocompatibility complex-mismatched allo-HSCT model. Furthermore, baricitinib (an inhibitor of Janus kinases 1 and 2 (JAK1/JAK2) downstream of IFNγR/IL6R) completely prevented GvHD; expanded regulatory T cells by preserving JAK3-STAT5 signaling; downregulated CXCR3 and helper T cells 1 and 2 while preserving allogeneic antigen-presenting cell-stimulated T-cell proliferation; and suppressed the expression of major histocompatibility complex II (I-Ad), CD80/86, and PD-L1 on host antigen-presenting cells. Baricitinib also reversed established GvHD with 100% survival, thus demonstrating both preventive and therapeutic roles for this compound. Remarkably, baricitinib enhanced the GvL effects, possibly by downregulating tumor PD-L1 expression.

PMID:
29691471
PMCID:
PMC6168427
DOI:
10.1038/s41375-018-0123-z
[Indexed for MEDLINE]
Free PMC Article

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