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STEM CELL TRANSPLANTATION

Baricitinib prevents GvHD by increasing Tregs via JAK3 and treats established GvHD by promoting intestinal tissue repair via EGFR

Leukemia volume 36, pages 292–295 (2022)Cite this article

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Since BARI significantly increases Tregs during the first two weeks of the treatment [5], we hypothesized that two weeks of BARI administration would be sufficient to prevent GvHD. To test our hypothesis, we treated allo-HSCT recipient mice with BARI for a period of one, two, three, or four weeks following allo-HSCT. Although all mice treated with BARI demonstrated significantly improved overall survival rates and clinical GvHD scores compared to vehicle control (Fig. 1C), two weeks of BARI treatment had a similar preventative effect as that of three or four weeks. Thus, we conclude that two weeks of BARI treatment is sufficient to prevent GvHD. We also observed a significantly improved multilineage engraftment (especially platelets) as well as full donor chimerism in the BARI-treated groups compared to vehicle control (Supplementary Fig. 3a, b). In addition, all BARI-treated mice showed significantly decreased percentages of donor bone marrow (BM)-derived CD4/CD8 double-negative cells in the peripheral blood compared to vehicle control (Supplementary Fig. 3b), suggesting that BARI reduces thymic damage. Furthermore, higher percentages of donor BM-derived T/B lymphocytes were observed in BARI-treated groups compared to vehicle control, which is consistent with less clinical GvHD (Supplementary Fig. 3b).

Gastrointestinal (GI) GvHD is associated with the amplification of systemic GvHD by propagating pro-inflammatory cytokines, and thus with substantial morbidity and mortality in allo-HSCT recipients [8,9,10]. Therefore, we next sought to determine the mechanisms by which BARI reverses established GvHD in the GI tract. We confirmed that D10 group showed reduced histological GvHD grades in GI as well as overall histological GvHD grades compared to vehicle control (Supplementary Fig. 5a, b). In contrast, D17 group was not significantly different in overall histological GvHD grades from vehicle control (Supplementary Fig. 5a, b). GI GvHD is often associated with crypt cell degeneration and intestinal stem cell (ISC) loss, which leads to dysregulation in the intestinal homeostasis and microbiota as well as epithelial barrier function [8, 10, 11]. We found that the numbers of ISCs and Paneth cells were significantly decreased by allogeneic T cell-mediated GI damage on days 10 and 17 after allo-HSCT (Supplementary Fig. 6a, b). Crypt depth was recovered by day 17 as the crypt depth of the BM only group on day 10 was only half that of the BM only group on day 17, while donor T cells prevented its recovery on day 17 (Supplementary Fig. 6a, b). The numbers of both ISCs and Paneth cells and crypt depth were significantly increased by BARI compared to vehicle control when examined after two weeks of treatment (Supplementary Fig. 6c, d). In addition, the integral optical density (IOD) of OLFM4, a marker of ISCs, was significantly increased by BARI compared to vehicle control (Fig. 2B). We next examined the direct effect of BARI and RUX on cell growth and proliferation of intestinal epithelial cells using human intestinal organoids derived from healthy donors. We found that both BARI and RUX significantly increased the growth of colonoids derived from rectum and enteroids derived from ileum (Supplementary Fig. 7a). In addition, BARI directly increased the recovery of ISCs damaged by irradiation in vivo (Supplementary Fig. 7b).

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Fig. 1: BARI increases GvHD-suppressive Tregs by preserving JAK3 signaling.
Fig. 2: Inhibition of EGFR signaling by erlotinib diminishes GvHD recovery mediated by BARI.

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Acknowledgements

JC is supported by Amy Strelzer Manasevit Research Program (the Be The Match Foundation and the National Marrow Donor Program), 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), Bigelow Aerospace (OTM 13489), Washington University SPORE-CDP in Leukemia (P50 CA171963), Washington University DDRCC grant (P30 DK052574), and the Bryan Thomas Campbell Foundation. JFD is supported by Bigelow Aerospace (OTM 13489), Washington University NCI/NIH SPORE in Leukemia (P50 CA171963), NCI Outstanding Investigator Award (R35 CA210084), and the Bryan Thomas Campbell Foundation. KA is supported by Washington University SPORE Diversity Program (P50 CA171963). MAC is supported by R01DK109384 and The Lawrence C. Pakula MD IBD Research Fund at Washington University.

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Author notes

  1. These authors contributed equally: Sena Kim, Kidist Ashami

Authors and Affiliations

  1. Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA

    Sena Kim, Kidist Ashami, Sora Lim, Karl Staser, Kiran Vij, Julie Ritchey, Sarah Peterson, Matthew L. Cooper, John F. DiPersio & Jaebok Choi

  2. Division of Dermatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA

    Karl Staser

  3. Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA

    Feng Gao

  4. Inflammatory Bowel Diseases Center and Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA

    Srikanth Santhanam & Matthew A. Ciorba

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Contributions

Conceptualization: JFD and JC; methodology: SK, KA, JFD and JC; investigation and validation: SK, KA, SL, KS, KV, SS, JR, SP, FG, MAC, JC; formal analysis: SK, KA, SL, KS, KV, SS, JC; writing for the first version of the manuscript: SK, KA, JC; visualization: SK, KA, SL, KS, JC; supervision: JC; funding acquisition: JFD and JC.

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Correspondence to Jaebok Choi.

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Competing interests

JC received honorarium from Incyte Corporation, received research funding from Mallinckrodt Pharmaceuticals, and served as a consultant for Daewoong Pharmaceutical. JFD served on advisory boards for Incyte Corporation, CellWorks, Macrogenics, Amphivena, Arch, Rivervest, and Bioline and is a co-Founder of Magenta Therapeutics and WUGen. MLC is a co-Founder and Chief Scientific Officer of WUgen. MAC previously had research grants from Incyte Corporation. The other authors declare no conflict of interest.

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Kim, S., Ashami, K., Lim, S. et al. Baricitinib prevents GvHD by increasing Tregs via JAK3 and treats established GvHD by promoting intestinal tissue repair via EGFR. Leukemia 36, 292–295 (2022). https://doi.org/10.1038/s41375-021-01360-9

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