Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes
Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes
复制标题
DOI：
10.1073/pnas.0908834106
复制
发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
S. Yokoyama;Nobumasa Watanabe;N. Sato;P. Perera;L. Filkoski;Toshiyuki Tanaka;M. Miyasaka;T. Waldmann;T. Hiroi;L. Perera
中科院分区：
文献类型：
--
作者：
S. Yokoyama;Nobumasa Watanabe;N. Sato;P. Perera;L. Filkoski;Toshiyuki Tanaka;M. Miyasaka;T. Waldmann;T. Hiroi;L. Perera
乳糜泻（CD）是一种自身免疫性炎症性疾病，尤其是在西半球具有相对较高的患病率。CD的发病机制中涉及强遗传成分，几乎所有发生疾病的个体携带编码特异性HLA-DQ 2或HLA-DQ 8异二聚体的HLA-DQ等位基因。食用富含谷蛋白的谷物会在遗传易感个体中引发慢性肠道炎症，导致CD的发展。新出现的证据表明，IL-15在CD炎症和组织破坏的协调和持续中起着核心作用。因此，IL-15是开发CD新疗法的一个有吸引力的靶点。在肠上皮细胞中特异性表达人IL-15的转基因小鼠（T3 b-hIL-15 Tg小鼠）发生绒毛萎缩和严重的十二指肠-空肠炎症，并在受影响的粘膜中大量积累NK样CD 8+淋巴细胞。我们使用这些小鼠来证明用结合鼠IL-2/IL-15 R β（CD 122）的抗体（TM-β1）阻断IL-15信号传导导致自身免疫性肠损伤的逆转。本研究，沿着其他人的工作，提供了探索IL-15阻断的基本原理，作为对IL-15的不受控制的表达在难治性CD的发病机制和维持中至关重要的假设的检验。
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 (T3b-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-β1) 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.