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Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS)

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Abstract

Purpose

Autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant genetic disorder of lymphocyte homeostasis with defective Fas-mediated apoptosis. Current therapies for ALPS primarily target autoimmune manifestations with non-specific immune suppressants with variable success thus highlighting the need for better therapeutics for this disorder.

Methods

The spectrum of clinical manifestations of ALPS is mirrored by MRL/lpr mice that carry a loss of function mutation in the Fas gene and have proven to be a valuable model in predicting the efficacy of several therapeutics that are front-line modalities for the treatment of ALPS. We evaluated the potential efficacy of tofacitinib, an orally active, pan-JAK inhibitor currently approved for rheumatoid arthritis as a single agent modality against ALPS using MRL/lpr mice.

Results

We demonstrate that a 42-day course of tofacitinib therapy leads to a lasting reversal of lymphadenopathy and autoimmune manifestations in the treated MRL/lpr mice, Specifically, in treated mice the peripheral blood white blood cell counts were reversed to near normal levels with almost a 50 % reduction in the TCRαβ+CD4−CD8−T lymphocyte numbers that coincided with a parallel increase in CD8+ T cells without a demonstrable effect on CD4+ lymphocytes including FoxP3+ regulatory T cells. The elevated plasma IgG and IgA levels were also drastically lowered along with a significant reduction in plasmablasts and plasmacytes in the spleen.

Conclusion

On the basis of these results, it is likely that tofacitinib would prove to be a potent single agent therapeutic modality capable of ameliorating both offending lymphadenopathy as well as autoimmunity in ALPS patients.

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Abbreviations

ALPS:

Autoimmune lymphoproliferative syndrome

DN:

Double negative

SLE:

Systemic lupus erythematosus

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Acknowledgments

This research was supported in part by the intramural programs of the National Cancer Institute and a Grant-in-Aid for 2009 Multidisciplinary Research Project from MEXT in Japan from the Ministry of Education, Science, Sports, and Culture of Japan (T. Hiroi). L.P. Perera gratefully acknowledges the receipt of an invitational fellowship from the Japan Society for the Promotion of Science.

Authorship Contributions

S.Y., P-Y.P., S.T., N.W., O.K., T.A.W., T.H., and L.P.P. designed experiments and interpreted the data; S.Y., S.T., N.W., O.K., and L.P.P. performed experiments; L.P.P. supervised the study and wrote the paper.

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Conflict of Interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Genome Medicine, The Tokyo Metropolitan Institute of Medical Science, 2-1-6, kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan

    Seiji Yokoyama, Seigo Terawaki, Nobumasa Watanabe, Osamu Kaminuma & Takachika Hiroi

  2. Veterans Affairs Medical Center, Washington, DC, 20422, USA

    Pin-Yu Perera

  3. Lymphoid Malignancies Branch, National Cancer Institute, Bldg 10 4N114, Bethesda, MD, 20892-1374, USA

    Thomas A. Waldmann & Liyanage P. Perera

Authors
  1. Seiji Yokoyama
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  2. Pin-Yu Perera
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  3. Seigo Terawaki
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  4. Nobumasa Watanabe
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  5. Osamu Kaminuma
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  6. Thomas A. Waldmann
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  7. Takachika Hiroi
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  8. Liyanage P. Perera
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Corresponding authors

Correspondence to Takachika Hiroi or Liyanage P. Perera.

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Yokoyama, S., Perera, PY., Terawaki, S. et al. Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS). J Clin Immunol 35, 661–667 (2015). https://doi.org/10.1007/s10875-015-0203-z

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  • DOI: https://doi.org/10.1007/s10875-015-0203-z

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