α4β7 阻断对肠道淋巴细胞亚群和淋巴组织发育的影响。
Effect of α4β7 blockade on intestinal lymphocyte subsets and lymphoid tissue development.
机构信息
Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
出版信息
Inflamm Bowel Dis. 2010 Oct;16(10):1751-62. doi: 10.1002/ibd.21266.
BACKGROUND
Blockade of the integrin α4β7 has promise as a therapy for inflammatory bowel disease. α4β7 plays diverse roles in the intestinal immune system, including lymphocyte homing and lymphoid tissue formation; however, the effects of α4β7 blockade on these processes during inflammation and their relationship to the efficacy of α4β7 blockade and its potential untoward effects are largely unknown.
METHODS
α4β7 function was inhibited by genetic manipulation or antibody blockade. The effects of these manipulations on lymphoid tissues and the presence of lymphocyte subpopulations in the murine small intestine and colon were evaluated in the unchallenged state, during the acute injury dextran sodium sulfate model, and during the splenocyte transfer chronic inflammation model.
RESULTS
α4β7 inhibition resulted in a decrease in the B-lymphocyte population in the diffuse lamina propria and a decrease in the number of lymphoid aggregates in the uninflamed intestine and in the acute injury model. α4β7 blockade did not reduce the Foxp3- T-lymphocyte population but did decrease the Foxp3+ T-lymphocyte population located selectively within the lymphoid aggregates in the uninflamed intestine and in the acute injury model. In contrast, α4β7 blockade reduced the intestinal T-lymphocyte population and decreased the production of inflammatory cytokines in the T-lymphocyte mediated chronic inflammation model.
CONCLUSIONS
These findings demonstrate differential use of α4β7 by B-lymphocytes, Foxp3- T-lymphocytes, and Foxp3+ T-lymphocytes to home to the gut, and suggest that α4β7 blockade may serve as a targeted therapy that selectively inhibits the accumulation of pathogenic T-lymphocyte populations in the chronically inflamed intestine.
背景
阻断整合素 α4β7 有望成为治疗炎症性肠病的一种疗法。α4β7 在肠道免疫系统中发挥着多种作用，包括淋巴细胞归巢和淋巴组织形成；然而，α4β7 阻断在炎症过程中对这些过程的影响及其与 α4β7 阻断疗效的关系及其潜在的不良影响在很大程度上尚不清楚。
方法
通过基因操作或抗体阻断来抑制 α4β7 的功能。在未受挑战的状态下、在葡聚糖硫酸钠急性损伤模型期间以及在脾细胞转移慢性炎症模型期间，评估这些操作对肠道淋巴组织和肠道固有层和结肠中小淋巴细胞亚群存在的影响。
结果
α4β7 抑制导致弥漫性固有层 B 淋巴细胞数量减少，未受炎症影响的肠道和急性损伤模型中淋巴样聚集物数量减少。α4β7 阻断不会减少 Foxp3+ T 淋巴细胞群体，但会选择性地减少未受炎症影响的肠道和急性损伤模型中淋巴样聚集物内的 Foxp3+ T 淋巴细胞群体。相比之下，α4β7 阻断减少了肠道 T 淋巴细胞群体，并减少了 T 淋巴细胞介导的慢性炎症模型中炎症细胞因子的产生。
结论
这些发现表明 B 淋巴细胞、Foxp3- T 淋巴细胞和 Foxp3+ T 淋巴细胞对肠道归巢有不同的 α4β7 利用，表明 α4β7 阻断可能作为一种靶向治疗方法，选择性地抑制慢性炎症肠道中致病性 T 淋巴细胞群体的积累。
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