テラワキ　セイゴウ   Seigo Terawaki   寺脇　正剛    所属   川崎医科大学  医学部 基礎医学　分子遺伝医学    職種   特任講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS).
掲載誌名	正式名：Journal of clinical immunology 略　 称：J Clin Immunol ISSNコード：15732592/02719142
掲載区分	国外
巻・号・頁	35(7),pp.661-667
著者・共著者	Yokoyama Seiji, Perera Pin-Yu, Terawaki Seigo, Watanabe Nobumasa, Kaminuma Osamu, Waldmann Thomas A, Hiroi Takachika, Perera Liyanage P
発行年月	2015/10
概要	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