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

• DOI: 10.1038/s41375-018-0123-z
• Publication Date: 2018-04-04T02:01:53Z
• Authors: Jaebok Choi; Matthew L. Cooper; Karl Staser; Kidist Ashami; Kiran R. Vij; Bing Wang; Lynne Marsala; Jessica Niswonger; Julie Ritchey; Bader Alahmari; Samuel Achilefu; Ikuo Tsunoda; Mark A. Schroeder; John F. DiPersio
• Keywords: Male; 0301 basic medicine; Sulfonamides; 0303 health sciences; Hematopoietic Stem Cell Transplantation; Antigen-Presenting Cells; Graft vs Host Disease; Janus Kinase 1; Receptors, Interleukin-6; T-Lymphocytes, Regulatory; Article; B7-H1 Antigen; 3. Good health; Mice; 03 medical and health sciences; Purines; B7-1 Antigen; Animals; Azetidines; Pyrazoles; B7-2 Antigen; Cells, Cultured; Cell Proliferation; Receptors, Interferon; Signal Transduction

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.