title: Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS).
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Genome Medicine, The Tokyo Metropolitan Institute of Medical Science, 2-1-6, kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Veterans Affairs Medical Center, Washington, DC, 20422, USA.
authors.forename: Pin-Yu
authors.initials: PY
authors.lastname: Perera
authors.affiliation: Department of Genome Medicine, The Tokyo Metropolitan Institute of Medical Science, 2-1-6, kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Terawaki
authors.affiliation: Department of Genome Medicine, The Tokyo Metropolitan Institute of Medical Science, 2-1-6, kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Department of Genome Medicine, The Tokyo Metropolitan Institute of Medical Science, 2-1-6, kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kaminuma
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, Bldg 10 4N114, Bethesda, MD, 20892-1374, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.affiliation: Department of Genome Medicine, The Tokyo Metropolitan Institute of Medical Science, 2-1-6, kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. hiroi-tk@igakuken.or.jp.
authors.forename: Takachika
authors.initials: T
authors.lastname: Hiroi
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, Bldg 10 4N114, Bethesda, MD, 20892-1374, USA. pereral@mail.nih.gov.
authors.forename: Liyanage P
authors.initials: LP
authors.lastname: Perera
mesh_terms: D000818:Animals; D056735:Autoimmune Lymphoproliferative Syndrome / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009154:Mutation / Q000235:genetics; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000502:physiology; D019014:fas Receptor / Q000235:genetics
chemical_list: C491899:Fas protein, mouse; D007136:Immunoglobulins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D019014:fas Receptor; C479163:tofacitinib; D053616:Janus Kinase 3
keywords: ALPS; Autoimmunity; SLE; lymphoproliferation; tofacitinib