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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes
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Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes

机译:抗体介导的IL-15阻断可逆转肠上皮细胞中过表达IL-15的转基因小鼠的自身免疫性肠损伤

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摘要

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 het-erodimers. 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-hlL-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.
机译:腹腔疾病(CD)是一种自身免疫性炎性疾病,患病率较高,尤其是在西半球。实际上,CD的发病机制涉及一个很强的遗传成分,几乎所有患有这种疾病的人都携带带有编码特定HLA-DQ2或HLA-DQ8杂二聚体的HLA-DQ等位基因。食用富含谷蛋白的谷物会触发遗传易感个体的慢性肠道炎症,从而导致CD的发展。越来越多的证据表明,IL-15在炎症的编排和永存以及CD的组织破坏中起着核心作用。因此,IL-15代表了开发用于CD的新疗法的有吸引力的靶标。在肠上皮细胞中特异性表达人IL-15的转基因小鼠(T3〜b-hlL-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聚NK样CD8〜+淋巴细胞。我们使用这些小鼠来证明用与鼠IL-2 / IL-15Rbeta(CD122)结合的抗体(TM-β1)阻断IL-15信号传导可逆转自身免疫性肠道损伤。本研究与其他研究一起,为探讨IL-15阻滞提供了理论依据,以检验IL-15不受控制的表达在难治性CD的发病机理和维持中至关重要的假说。

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