title: Tofacitinib, a janus kinase inhibitor demonstrates efficacy in an IL-15 transgenic mouse model that recapitulates pathologic manifestations of celiac disease.
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 (T3(b)-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 T3(b)-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.
authors.affiliation: Department of Allergy and Immunology, 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.forename: Pin-Yu
authors.initials: PY
authors.lastname: Perera
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Takachika
authors.initials: T
authors.lastname: Hiroi
authors.forename: Liyanage P
authors.initials: LP
authors.lastname: Perera
mesh_terms: D000818:Animals; D002446:Celiac Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000235:genetics* / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D019409:Interleukin-15; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053612:Janus Kinases