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Specificity of JAK-kinase inhibition determines impact on human and murine T-cell function

Leukemia volume 30, pages 991–995 (2016)Cite this article

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Clinical use of Janus-Kinase- (JAK-) inhibitors has significantly improved the therapeutic options for inflammation driven diseases. Particularly inhibitors of JAKs 1 and 2 are in clinical use and (at least one of them) already approved for certain myeloproliferative neoplasms (MPNs) such as primary myelofibrosis or polycythemia vera.1, 2, 3 JAKs are essential for cytokine-induced intracellular signaling of lymphocytes4 and their inactivation leads to impairment of immune cell function. Reduction of T-cell reactivity became evident when treating Graft-versus-Host disease (GvHD) in vivo with the JAK1/2-inhibitor ruxolitinib (RUX).5 Most recent reports have highlighted that RUX constrains T-cell activation and function in MPN patients.6 Further clinical indicators of impaired T-cell function are severe infections emerging in JAK-inhibitor treated patients among which herpes virus reactivation, cryptococcus neoformans pneumonia, toxoplasmosis retinitis and disseminated tuberculosis are the most alarming.2, 7, 8, 9, 10 Ongoing pre-clinical and clinical development of more selective JAK111 or JAK212 inhibitors may offer higher efficacy, however, specificity of JAK inhibition may severely influence the emergence of severe infectious complications.

We hypothesized that specificity of JAK inhibition may severely influence the observed immunosuppressive effects.

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Acknowledgements

This work was supported by a grant from Novartis Inc. to DW and FHH and by the DFG-Collaborative Research Center (CRC854) to BI (Project A26), BS (Projects B12 and B19) and TF and FHH (Project A20). All human samples were collected and stored in the Hematology Tissue-Bank Magdeburg (HTM) supported by a grant from the Jose-Carreras Foundation (SP12/04) to FHH.

Author contributions

FP, TMS, SR, DW, CE, MCP, SF, AP, CF and US performed research. FP, MCP, BS, BI, TF analyzed data and contributed to the writing of the manuscript. FHH designed research, analyzed data and wrote the paper.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Otto-von-Guericke University Medical Center, Magdeburg, Germany

    F Perner, T M Schnöder, D Wolleschak, C Ebert, S Frey, A Polanetzki, C Fahldieck, U Schönborn, T Fischer & F H Heidel

  2. Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Medical Center, Magdeburg, Germany

    S Ranjan & B Isermann

  3. Mouse-Pathology, Animal Experimental Unit, Helmholtz-Center for Infection Research (HZI), Braunschweig, Germany

    M C Pils

  4. Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Medical Center, Magdeburg, Germany

    B Schraven

  5. Department of Immune Control, Helmholtz-Center for Infection Research (HZI), Braunschweig, Germany

    B Schraven

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  1. F Perner
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Corresponding author

Correspondence to F H Heidel.

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Competing interests

FHH and DW received research funding from Novartis Inc. FHH is an advisory board member for Novartis Inc. The remaining authors declare no conflict of interest.

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Perner, F., Schnöder, T., Ranjan, S. et al. Specificity of JAK-kinase inhibition determines impact on human and murine T-cell function. Leukemia 30, 991–995 (2016). https://doi.org/10.1038/leu.2015.218

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