Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Section for Parasitology, Health and Development Department of Veterinary Disease Biology, University of Copenhagen, Denmark.
Mol Immunol. 2014 Jul;60(1):1-7. doi: 10.1016/j.molimm.2014.03.003. Epub 2014 Apr 2.
The administration of helminths is considered a promising strategy for the treatment of autoimmune diseases due to their immunomodulatory properties. Currently, the application of the helminth Trichuris suis as a treatment for Crohn's disease is being studied in large multi-center clinical trials. The intestinal epithelium forms an efficient barrier between the intestinal lumen containing the microbial flora and helminths, and dendritic cells (DCs) present in the lamina propria that determine the TH response. Here, we investigated how excreted/secreted (E/S) products of T. suis affect the barrier function of intestinal epithelial cells (IECs) in order to reach the DCs and modulate the immune response. We show that T. suis E/S products reduce the barrier function and the expression of the tight junction proteins EMP-1 and claudin-4 in IEC CMT93/69 monolayers in a glycan-dependent manner. This resulted in an increased passage of soluble compounds to the basolateral side that affected DC function. In addition, T. suis E/S suppressed LPS-induced pro-inflammatory cytokine production by CMT93/69 cells, whereas the production of the TH2 response-inducing cytokine thymic stromal lymphopoietin (TSLP) was induced. Our studies indicate that T. suis E/S glycans affect the function of the intestinal epithelium in order to modulate DC function. Identification of the T. suis E/S glycans that modulate IEC and DC function may lead to a strategy to reduce symptoms of autoimmune and allergic immune diseases by orally administrated helminth-derived factors without the need of infection with live helminths.
寄生虫的管理被认为是治疗自身免疫性疾病的一种有前途的策略，因为它们具有免疫调节特性。目前，正在进行大型多中心临床试验，研究用寄生虫旋毛虫（Trichuris suis）治疗克罗恩病。肠道上皮细胞在含有微生物菌群和寄生虫的肠腔与位于固有层的树突状细胞（DC）之间形成有效的屏障，而 DC 决定 TH 反应。在这里，我们研究了旋毛虫的排泄/分泌（E/S）产物如何影响肠道上皮细胞（IEC）的屏障功能，以到达 DC 并调节免疫反应。我们发现，旋毛虫的 E/S 产物以糖依赖性方式降低肠道上皮细胞 CMT93/69 单层的屏障功能和紧密连接蛋白 EMP-1 和 Claudin-4 的表达。这导致可溶性化合物向基底外侧侧的通透性增加，从而影响 DC 功能。此外，旋毛虫 E/S 抑制 CMT93/69 细胞中 LPS 诱导的促炎细胞因子产生，而诱导 TH2 反应诱导细胞因子胸腺基质淋巴细胞生成素（TSLP）的产生。我们的研究表明，旋毛虫的 E/S 糖影响肠道上皮细胞的功能，以调节 DC 功能。鉴定调节 IEC 和 DC 功能的旋毛虫 E/S 糖可能会导致一种策略，即通过口服给予寄生虫衍生因子来减轻自身免疫和过敏免疫性疾病的症状，而无需感染活寄生虫。
