Seiji Yokoyama1, Pin-Yu Perera2, Seigo Terawaki1, Nobumasa Watanabe1, Osamu Kaminuma1, Thomas A Waldmann3, Takachika Hiroi4, Liyanage P Perera5. 1. Department of Genome Medicine, The Tokyo Metropolitan Institute of Medical Science, 2-1-6, kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. 2. Veterans Affairs Medical Center, Washington, DC, 20422, USA. 3. Lymphoid Malignancies Branch, National Cancer Institute, Bldg 10 4N114, Bethesda, MD, 20892-1374, USA. 4. 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. 5. Lymphoid Malignancies Branch, National Cancer Institute, Bldg 10 4N114, Bethesda, MD, 20892-1374, USA. pereral@mail.nih.gov.
Abstract
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.
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/lprmice 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/lprmice. 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/lprmice, 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 ALPSpatients.
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