論文

査読有り
2015年10月

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

JOURNAL OF CLINICAL IMMUNOLOGY
  • Seiji Yokoyama
  • ,
  • Pin-Yu Perera
  • ,
  • Seigo Terawaki
  • ,
  • Nobumasa Watanabe
  • ,
  • Osamu Kaminuma
  • ,
  • Thomas A. Waldmann
  • ,
  • Takachika Hiroi
  • ,
  • Liyanage P. Perera

35
7
開始ページ
661
終了ページ
667
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1007/s10875-015-0203-z
出版者・発行元
SPRINGER/PLENUM PUBLISHERS

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 TCR alpha beta(+)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.

リンク情報
DOI
https://doi.org/10.1007/s10875-015-0203-z
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000363976500009&DestApp=WOS_CPL
ID情報
  • DOI : 10.1007/s10875-015-0203-z
  • ISSN : 0271-9142
  • eISSN : 1573-2592
  • Web of Science ID : WOS:000363976500009

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