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Itacitinib prevents xenogeneic GVHD in humanized mice

Bone Marrow Transplantation volume 56, pages 2672–2681 (2021)Cite this article

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Abstract

We assessed the impact of the Janus Kinase (JAK) 1 inhibitor itacitinib on xenogeneic graft-versus-host disease (xGVHD). XGVHD was induced by i.v. injection 20 × 106 human peripheral blood mononuclear cells (hPBMC) in NSG mice on day 0. Itacitinib (3 mg, ≈120 mg/kg) or methylcellulose was administered by force-feeding twice a day from day 3 to day 28. Mice were followed for xGVHD score and survival. In addition, human T-cell engraftment and as well as human T-cell subtypes were monitored in blood on days 14, 21, and 28 after transplantation. We observed that itacitinib-treated mice had significantly longer survival than control mice (median 45 versus 33 days; P < 0.001). Further, they also had lower absolute numbers of human CD4+ T cells on days 21 and 28 after transplantation as well as of human CD8+ T cells on days 14, 21, and 28 after transplantation. In addition, itacitinib-treated mice had higher frequencies of human regulatory T cells (Treg) on days 21 and 28 after transplantation. In summary, our data indicate that itacitinib decreases human T-cell engraftment, increases Treg frequencies and attenuates xGVHD in NSG mice transplanted with hPBMC.

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Fig. 1: Impact of itacitinib on xGVHD.
Fig. 2: T-SNE of CD4+ T cells in peripheral blood from mice in cohort 3 on day 28 after transplantation.
Fig. 3: T-SNE of CD8+ T cells in peripheral blood from mice in cohort 3 on day 28 after transplantation.
Fig. 4: Impact of itacitinib on GvL effects.

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Data availability

The datasets supporting the conclusions of this article are included within the article and its additional files. Raw files used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to Sandra Ormenese, Raafat Stephan, and Céline Vanwinge from the Imaging and Flow Cytometry Platform of the GIGA for help with flow cytometry analyses. We are also grateful to INCYTE Biosciences who kindly gave us itacitinib.

Funding

This study was supported by funds from: the National Fund for Scientific Research (FNRS) (grant numbers T.0069.15 and T.0016.20), The Belgian Fondation contre le cancer (grant # FBC # FAF-C/2016/889), and the Leon Fredericq fund and Anti-Cancer Center at the University of Liège. GE is a Télévie Research Assistant, and FB is a senior research associate of the National Fund for Scientific Research (FNRS) Belgium.

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Author notes

  1. These authors contributed equally: Justine Courtois, Caroline Ritacco

Authors and Affiliations

  1. Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège, Belgium

    Justine Courtois, Caroline Ritacco, Sophie Dubois, Lorenzo Canti, Benoît Vandenhove, Coline Daulne, Jo Caers, Sophie Servais, Yves Beguin, Grégory Ehx & Frédéric Baron

  2. Department of Statistics, University of Liège, Liège, Belgium

    Laurence Seidel

  3. Department of Medicine, Division of Hematology, CHU of Liège, Liège, Belgium

    Jo Caers, Sophie Servais, Yves Beguin & Frédéric Baron

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Contributions

FB designed the study; JC, CR, and SD performed the experiments; LC, BV, and CD helped in the experiments; JC, LS and CR analyzed the data; JC, CR, GE, and FB interpreted the data; SS, JCA and YB helped in data interpretation; FB and JC wrote the article; all authors reviewed and edited the manuscript.

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Correspondence to Frédéric Baron.

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Conflict of interest

Frédéric Baron has received travel grants from Celgene, Abbvie, Novartis, INCYTE Biosciences, and Sanofi as well as honoraria from Merck and Abbvie. The remaining authors declare that they have no relevant conflict of interest in regard to this study.

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Courtois, J., Ritacco, C., Dubois, S. et al. Itacitinib prevents xenogeneic GVHD in humanized mice. Bone Marrow Transplant 56, 2672–2681 (2021). https://doi.org/10.1038/s41409-021-01363-1

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