Seigo Terawaki
Department Kawasaki Medical School Kawasaki Medical School, Department of Molecular and Genetic Medicine, Position Assistant Professor with Special Assignment |
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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 |