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.
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J.C. is supported by the Amy Strelzer Manasevit Research Program, which is funded through the Be The Match Foundation and the National Marrow Donor Program; the Rays of Hope St. Baldrick’s Research Grant (St. Baldrick’s Foundation); Washington University SPORE-CDP (P50 CA171963-01); Washington University DDRCC grant (P30 DK052574); Alvin J. Siteman Cancer Center Siteman Investment Program (supported by the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, National Cancer Institute Cancer Center Support Grant, P30 CA091842, and Barnard Trust); and the Bryan Thomas Campbell Foundation. J.F.D. is supported by the National Cancer Institute (P50 CA94056-09, R35 CA210084-01, P01 CA101937 and P50 CA171963-01) and the Bryan Thomas Campbell Foundation. L.M. and S.A. are supported by the National Institutes of Health (P50 CA94056). I.T. is supported by the National Institute of General Medical Sciences COBRE Grant (P30-GM110703) and the Japan Society for the Promotion of Science (Grants-in-Aid for Scientific Research-KAKENHI, 16H07356). We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO for the use of the immunomonitoring laboratory, which provided the cytokine analysis service. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA091842. We thank Jennifer Gann of Gann Editorial Group (St. Louis, MO) for editorial assistance.
Conceptualization: J.C., M.L.C., and J.F.D.; methodology: J.C., M.L.C., and J.F.D.; investigation and validation: J.C., M.L.C., K.S., K.A., K.R.V., B.W., L.M., J.N., J.R., and B.A.; formal analysis: J.C., M.L.C., K.S., and L.M.; resources: S.A. and I.T.; writing—original draft: J.C., M.L.C., and J.F.D.; writing—review and editing: J.C., M.L.C., K.S., S.A., I.T., M.A.S., and J.F.D.; visualization: J.C., M.L.C., K.S., K.R.V., and L.M.; supervision: J.C. and J.F.D.; funding acquisition: J.C. and J.F.D.
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The authors declare that they have no conflict of interest.
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Choi, J., Cooper, M.L., Staser, K. et al. Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 32, 2483–2494 (2018). https://doi.org/10.1038/s41375-018-0123-z
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