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Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15849-54. doi: 10.1073/pnas.0908834106. Epub 2009 Sep 1.

Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes.

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  • 1Department of Allergy and Immunology, Tokyo Metropolitan Institute of Medical Science, Tokyo, 113-8613, Japan.

Abstract

Celiac disease (CD) is an autoimmune inflammatory disease with a relatively high prevalence especially in the western hemisphere. A strong genetic component is involved in the pathogenesis of CD with virtually all individuals that develop the disease carrying HLA-DQ alleles that encode specific HLA-DQ2 or HLA-DQ8 heterodimers. Consumption of cereals rich in gluten triggers a chronic intestinal inflammation in genetically susceptible individuals leading to the development of CD. Emerging evidence has implicated a central role for IL-15 in the orchestration and perpetuation of inflammation and tissue destruction in CD. Therefore, IL-15 represents an attractive target for development of new therapies for CD. Transgenic mice that express human IL-15 specifically in enterocytes (T3(b)-hIL-15 Tg mice) develop villous atrophy and severe duodeno-jejunal inflammation with massive accumulation of NK-like CD8(+) lymphocytes in the affected mucosa. We used these mice to demonstrate that blockade of IL-15 signaling with an antibody (TM-beta1) that binds to murine IL-2/IL-15Rbeta (CD122) leads to a reversal of the autoimmune intestinal damage. The present study, along with work of others, provides the rationale to explore IL-15 blockade as a test of the hypothesis that uncontrolled expression of IL-15 is critical in the pathogenesis and maintenance of refractory CD.

PMID:
19805228
[PubMed - indexed for MEDLINE]
PMCID:
PMC2736142
Free PMC Article

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