Journal of Clinical Immunology

, Volume 35, Issue 7, pp 661–667 | Cite as

Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS)

  • Seiji Yokoyama
  • Pin-Yu Perera
  • Seigo Terawaki
  • Nobumasa Watanabe
  • Osamu Kaminuma
  • Thomas A. Waldmann
  • Takachika Hiroi
  • Liyanage P. Perera
Original Article



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.


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.


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+CD4CD8T 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.


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.


Autoimmunity lymphoproliferation ALPS tofacitinib SLE 



Autoimmune lymphoproliferative syndrome


Double negative


Systemic lupus erythematosus



This research was supported in part by the intramural programs of the National Cancer Institute and a Grant-in-Aid for 2009 Multidisciplinary Research Project from MEXT in Japan from the Ministry of Education, Science, Sports, and Culture of Japan (T. Hiroi). L.P. Perera gratefully acknowledges the receipt of an invitational fellowship from the Japan Society for the Promotion of Science.

Authorship Contributions

S.Y., P-Y.P., S.T., N.W., O.K., T.A.W., T.H., and L.P.P. designed experiments and interpreted the data; S.Y., S.T., N.W., O.K., and L.P.P. performed experiments; L.P.P. supervised the study and wrote the paper.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no competing financial interests.

Supplementary material

10875_2015_203_MOESM1_ESM.docx (1.2 mb)
ESM 1 (DOCX 1223 kb)


  1. 1.
    Canale VC, Smith CH. Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr. 1967;70:891–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Sneller MC, Straus SE, Jaffe ES, Jaffe JS, Fleisher TA, Stetler-Stevenson M, et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest. 1992;90:334–41.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995;268:1347–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Fisher GH, Rosenburg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81:935–46.CrossRefPubMedGoogle Scholar
  5. 5.
    Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rösen-Wolff A, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood. 2001;98:194–200.CrossRefPubMedGoogle Scholar
  6. 6.
    Madkaikar M, Mhatre S, Gupta M, Ghosh K. Advances in autoimmune lymphoproliferative syndromes. Eur J Haematol. 2011;87:1–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118:5741–51.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J, et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009;145:101–6.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Yokoyama S, Takada K, Hirasawa M, Perera LP, Hiroi T. Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease. J Clin Immunol. 2011;31:1038–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992;356:314–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Teachey DT, Obzut DA, Axsom K, Choi JK, Goldsmith KC, Hall J, et al. Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood. 2006;108:1965–71.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Dowdell KC, Pesnicak L, Hoffmann V, Steadman K, Remaley AT, Cohen JI, et al. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, diminishes lymphoproliferation in the Fas-deficient MRL/lpr(-/-) murine model of autoimmune lymphoproliferative syndrome (ALPS). Exp Hematol. 2009;37:487–94.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Holzelova E, Vonarbourg C, Stolzenberg MC, Arkwright PD, Selz F, Prieur AM, et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med. 2004;351:1409–18.CrossRefPubMedGoogle Scholar
  14. 14.
    Magerus-Chatinet A, Neven B, Stolzenberg MC, Daussy C, Arkwright PD, Lanzarotti N, et al. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation. J Clin Invest. 2011;121:106–12.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Hauck F, Magerus-Chatinet A, Vicca S, Rensing-Ehl A, Roesen-Wolff A, Roesler J, et al. Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation. Clin Immunol. 2013;147:61–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Rensing-Ehl A, Völkl S, Speckmann C, Lorenz MR, Ritter J, Janda A, et al. Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency. Blood. 2014;124:851–60.CrossRefPubMedGoogle Scholar
  17. 17.
    Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O’Shea JJ. Therapeutic targeting of Janus kinases. Immunol Rev. 2008;223:132–42.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186:4234–43.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495–507.CrossRefPubMedGoogle Scholar
  20. 20.
    Garbe K. Pfizer’s JAK inhibitor sails through phase 3 in rheumatoid arthritis. Nat Biotechnol. 2011;29:467–8.CrossRefGoogle Scholar
  21. 21.
    Sewgobind VD, Quaedackers ME, van der Laan LJ, Kraaijeveld R, Korevaar SS, Chan G, et al. The Jak inhibitor CP-690,550 preserves the function of CD4CD25FoxP3 regulatory T cells and inhibits effector T cells. Am J Transplant. 2010;10:1785–95.CrossRefPubMedGoogle Scholar
  22. 22.
    Bristeau-Leprince A, Mateo V, Lim A, Magerus-Chatinet A, Solary E, Fischer A, et al. Human TCR alpha/beta + CD4-CD8- double-negative T cells in patients with autoimmune lymphoproliferative syndrome express restricted Vbeta TCR diversity and are clonally related to CD8+ T cells. J Immunol. 2008;181:440–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Bleesing JJ, Brown MR, Dale JK, Straus SE, Lenardo MJ, Puck JM, et al. TCR-alpha/beta(+) CD4(-)CD8(-) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis. Clin Immunol. 2001;100:314–24.CrossRefPubMedGoogle Scholar
  24. 24.
    Marlies A, Udo G, Juergen B, Bernd S, Herrmann M, Haas JP. The expanded double negative T cell populations of a patient with ALPS are not clonally related to CD4+ or to CD8+ T cells. Autoimmunity. 2007;40:299–301.CrossRefPubMedGoogle Scholar
  25. 25.
    Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116:e35–40.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Price S, Shaw PA, Seitz A, Joshi G, Davis J, Niemela JE, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014;123:1989–99.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Boggio E, Clemente N, Mondino A, Cappellano G, Orilieri E, Gigliotti CL, et al. IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes. Blood. 2014;123:1178–86.CrossRefPubMedGoogle Scholar
  28. 28.
    Chavele KM, Merry E, Ehrenstein MR. Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production. J Immunol. 2015;194:2482–24855.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Stranges PB, Watson J, Cooper CJ, Choisy-Rossi CM, Stonebraker AC, Beighton RA, et al. Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity. 2007;26:629–41.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2015

Authors and Affiliations

  • Seiji Yokoyama
    • 1
  • Pin-Yu Perera
    • 2
  • Seigo Terawaki
    • 1
  • Nobumasa Watanabe
    • 1
  • Osamu Kaminuma
    • 1
  • Thomas A. Waldmann
    • 3
  • Takachika Hiroi
    • 1
  • Liyanage P. Perera
    • 3
  1. 1.Department of Genome MedicineThe Tokyo Metropolitan Institute of Medical ScienceSetagaya-kuJapan
  2. 2.Veterans Affairs Medical CenterWashingtonUSA
  3. 3.Lymphoid Malignancies BranchNational Cancer InstituteBethesdaUSA

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