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Tofacitinib, a Janus Kinase Inhibitor Demonstrates Efficacy in an IL-15 Transgenic Mouse Model that Recapitulates Pathologic Manifestations of Celiac Disease

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Abstract

Celiac disease (CD) is an immune-mediated, inflammatory disorder of the small intestines with a defined genetic etiological component associated with the expression of HLA-DQ2 and/or HLA-DQ8 haplotypes. The dietary consumption of gluten-rich cereals triggers a gluten-specific immune response in genetically susceptible individuals leading to a spectrum of clinical manifestations ranging from an inapparent subclinical disease, to overt enteropathy that can in some individuals progress to enteropathy-associated T cell lymphoma (EATL). The tissue-destructive pathologic process of CD is driven by activated NK-like intraepithelial CD8+ lymphocytes and the proinflammatory cytokine IL-15 has emerged to be pivotal in orchestrating this perpetual tissue destruction and inflammation. Moreover, transgenic mice that over-express human IL-15 from an enterocyte-specific promoter (T3b-hIL-15 Tg) recapitulate many of the disease-defining T and B cell-mediated pathologic features of CD, further supporting the evolving consensus that IL-15 represents a valuable target in devising therapeutic interventions against the form of the disease that is especially refractory to gluten-free diet. In the present study, we evaluated the potential efficacy of tofacitinib, a pan-JAK inhibitor that abrogates IL-15 signaling, as a therapeutic modality against CD using T3b-hIL-15 Tg mice. We demonstrate that tofacitinib therapy leads to a lasting reversal of pathologic manifestations in the treated mice, thereby highlighting the potential value of tofacitininb as a therapeutic modality against refractory CD for which no effective therapy exists currently. Additionally, the visceral adiposity observed in the tofacitinib-treated mice underscores the importance of continued evaluation of the drug’s impact on the lipid metabolism.

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Acknowledgments

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

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The authors declare no competing financial interests.

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Correspondence to Takachika Hiroi or Liyanage P. Perera.

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Supplementary Figure 1

Intermediate impact of tofacitinib treatment on CD4+ and CD8+ T lymphocytes. PBMC were isolated from T3b-hIL-15 Tg mice that were undergoing tofacitinib therapy at 10 and 20 days after the initiation of tofacitinib treatment and the impact of the drug on peripheral blood CD4+ and CD8+ T lymphocytes was assessed by flow cytometry. The modulation of these T cell subsets in three individual mice that were being treated with tofacitinib is shown. (PPT 1099 kb)

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Yokoyama, S., Perera, PY., Waldmann, T.A. et al. Tofacitinib, a Janus Kinase Inhibitor Demonstrates Efficacy in an IL-15 Transgenic Mouse Model that Recapitulates Pathologic Manifestations of Celiac Disease. J Clin Immunol 33, 586–594 (2013). https://doi.org/10.1007/s10875-012-9849-y

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  • DOI: https://doi.org/10.1007/s10875-012-9849-y

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