Faculty of Pharmacy, Université de Montréal, Montréal, Quebec, Canada.
Gastroenterology. 2012 Feb;142(2):316-25.e1-12. doi: 10.1053/j.gastro.2011.10.038. Epub 2011 Nov 10.
BACKGROUND & AIMS: Copolymers of hydroxyethyl methacrylate and styrene sulfonate complex with isolated gliadin (the toxic fraction of gluten) and prevent damage to the intestinal barrier in HLA-HCD4/DQ8 mice. We studied the activity toward gluten and hordein digestion and biologic effects of poly(hydroxyethyl methacrylate-co-styrene sulfonate (P(HEMA-co-SS)). We also investigated the effect of gliadin complex formation in intestinal biopsy specimens from patients with celiac disease.
We studied the ability of P(HEMA-co-SS) to reduce digestion of wheat gluten and barley hordein into immunotoxic peptides using liquid chromatography-mass spectrometry. The biodistribution and pharmacokinetic profile of orally administered P(HEMA-co-SS) was established in rodents using tritium-labeled polymer. We assessed the capacity of P(HEMA-co-SS) to prevent the immunologic and intestinal effects induced by a gluten-food mixture in gluten-sensitized HLA-HCD4/DQ8 mice after short-term and long-term administration. We measured the effects of gliadin complex formation on cytokine release ex vivo using intestinal biopsy specimens from patients with celiac disease.
P(HEMA-co-SS) reduced digestion of wheat gluten and barley hordein in vitro, thereby decreasing formation of toxic peptides associated with celiac disease. After oral administration to rodents, P(HEMA-co-SS) was predominantly excreted in feces, even in the presence of low-grade mucosal inflammation and increased intestinal permeability. In gluten-sensitized mice, P(HEMA-co-SS) reduced paracellular permeability, normalized anti-gliadin immunoglobulin A in intestinal washes, and modulated the systemic immune response to gluten in a food mixture. Furthermore, incubation of P(HEMA-co-SS) with mucosal biopsy specimens from patients with celiac disease showed that secretion of tumor necrosis factor-α was reduced in the presence of partially digested gliadin.
The copolymer P(HEMA-co-SS) reduced digestion of wheat gluten and barley hordein and attenuated the immune response to gluten in a food mixture in rodents. It might be developed to prevent or reduce gluten-induced disorders in humans.
羟乙基甲基丙烯酸酯和苯乙烯磺酸钠共聚物与分离的麦醇溶蛋白（谷蛋白的有毒部分）复合，防止 HLA-HCD4/DQ8 小鼠的肠屏障损伤。我们研究了共聚物对谷蛋白和麦醇溶蛋白消化的活性以及对其生物学效应。我们还研究了共聚物与乳糜泻患者肠活检标本中麦醇溶蛋白复合的作用。
我们使用液相色谱-质谱研究共聚物 P(HEMA-co-SS)降低小麦面筋和大麦麦醇溶蛋白消化成免疫毒性肽的能力。使用氚标记的聚合物在啮齿动物中建立口服 P(HEMA-co-SS)的体内分布和药代动力学特征。我们评估了共聚物在短期和长期给药后预防 HLA-HCD4/DQ8 小鼠对谷蛋白-食物混合物诱导的免疫和肠道效应的能力。我们使用乳糜泻患者的肠活检标本，体外测量共聚物形成麦醇溶蛋白复合物对细胞因子释放的影响。
共聚物 P(HEMA-co-SS)在体外降低了小麦面筋和大麦麦醇溶蛋白的消化，从而减少了与乳糜泻相关的毒性肽的形成。在给予啮齿动物口服后，共聚物 P(HEMA-co-SS)主要在粪便中排泄，即使存在低度黏膜炎症和增加的肠道通透性。在谷蛋白致敏的小鼠中，共聚物 P(HEMA-co-SS)降低了细胞旁通透性，使肠冲洗液中的抗麦醇溶蛋白免疫球蛋白 A 正常化，并调节食物混合物中对谷蛋白的全身免疫反应。此外，共聚物 P(HEMA-co-SS)与乳糜泻患者的黏膜活检标本孵育显示，在部分消化的麦醇溶蛋白存在下，肿瘤坏死因子-α的分泌减少。
共聚物 P(HEMA-co-SS)降低了小麦面筋和大麦麦醇溶蛋白的消化，并在啮齿动物的食物混合物中减弱了对谷蛋白的免疫反应。它可能被开发用于预防或减少人类对谷蛋白的诱导性疾病。
