Seigo Terawaki    Department   Kawasaki Medical School  Kawasaki Medical School, Department of Molecular and Genetic Medicine,    Position   Assistant Professor with Special Assignment
Article types	原著
Language	English
Peer review	Peer reviewed
Title	Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS).
Journal	Formal name：Journal of clinical immunology Abbreviation：J Clin Immunol ISSN code：15732592/02719142
Domestic / Foregin	Foregin
Volume, Issue, Page	35(7),pp.661-667
Author and coauthor	Yokoyama Seiji, Perera Pin-Yu, Terawaki Seigo, Watanabe Nobumasa, Kaminuma Osamu, Waldmann Thomas A, Hiroi Takachika, Perera Liyanage P
Publication date	2015/10
Summary	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.
DOI	10.1007/s10875-015-0203-z
PMID	26453583