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Transgenic Mice that Overexpress Human IL-15 in Enterocytes Recapitulate Both B and T Cell-Mediated Pathologic Manifestations of Celiac Disease

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Abstract

Celiac disease (CD) is a chronic immune-mediated intestinal inflammatory disorder afflicting genetically susceptible individuals triggered by the consumption of dietary cereals with high gluten content. As with many other organ-specific autoimmune diseases, the dominant tissue-destructive inflammation in CD is T cell-mediated. The proinflammatory cytokine IL-15 that is overexpressed in the intestinal epithelium of CD patients has emerged as a pivotal element that orchestrates intestinal inflammation and T cell-mediated autoimmune tissue destruction. Although no animal model exists that recapitulates the full spectrum of CD pathophysiology, we have previously reported that transgenic mice that overexpress human IL-15 in enterocytes (T3b-hlL-15 Tg) display many of the T cell-mediated pathologic features seen in CD. Extending these observations, we now report that T3b-hlL-15 Tg mice in addition to recapitulating T cell-mediated effects also display autoantibodies including those against tissue transglutaminase 2 and extensive lamina propria plasmacytosis, all of which are characteristic of CD, thereby reflecting the possibility that locally expressed IL-15 drives both T and B cell pathologic effects seen in CD. More importantly, these findings support the validity and utility of T3b-hlL-15 Tg mice as a reasonable model to investigate not only tissue-destructive pathologic processes in CD, but also to explore novel therapeutic modalities for the treatment of this disease.

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Abbreviations

CD:

Celiac disease

TG2:

Transglutaminase 2

IL-15:

Interleukin 15

RF:

Rheumatoid factor

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Acknowledgements

This work was supported by the research grants “Genomic for Agriculture Innovation GMC009” from the Ministry of Agriculture, Forestry and Fisheries of Japan 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, and a grant from the Ministry of Health, Labor and Welfare of Japan awarded to T. Hiroi. L.P. Perera gratefully acknowledges the receipt of an invitational fellowship from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Allergy and Immunology, The Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan

    Seiji Yokoyama & Takachika Hiroi

  2. Metabolism Branch, National Cancer Institute, Bldg. 10 4B40, Bethesda, MD, 20892-1374, USA

    Liyanage P. Perera

  3. Department of Microbiology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan

    Kazuko Takada & Masatomo Hirasawa

Authors
  1. Seiji Yokoyama
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  2. Kazuko Takada
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  3. Masatomo Hirasawa
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  4. Liyanage P. Perera
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  5. Takachika Hiroi
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Corresponding authors

Correspondence to Liyanage P. Perera or Takachika Hiroi.

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Yokoyama, S., Takada, K., Hirasawa, M. et al. Transgenic Mice that Overexpress Human IL-15 in Enterocytes Recapitulate Both B and T Cell-Mediated Pathologic Manifestations of Celiac Disease. J Clin Immunol 31, 1038–1044 (2011). https://doi.org/10.1007/s10875-011-9586-7

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  • DOI: https://doi.org/10.1007/s10875-011-9586-7

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