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

作者：Yokoyama Seiji; Watanabe Nobumasa; Sato Noriko; Perera Pin Yu; Filkoski Lyvouch; Tanaka Toshiyuki; Miyasaka Masayuki; Waldmann Thomas A; Hiroi Takachika^*; Perera Liyanage P

来源：Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(37): 15849-15854.

DOI：10.1073/pnas.0908834106

• autoimmunity
• celiac disease
• immunotherapy
• interleukine 15 receptor

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-beta 1) 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.

• 出版日期2009-9-15
• 单位河北医科大学