Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation. The therapeutic potential of PHCCC, however, is hindered by dose-limiting toxicity, poor solubility, and the need for frequent dosing. We hypothesized liposomal delivery of PHCCC might enable safe, effective delivery of this hydrophobic drug to exploit metabolism as a means of controlling inflammation in self-reactive immune cells. PHCCC was readily encapsulated in liposomes modified with polyethylene glycol. Under sink conditions, controlled release resulted in 58% of drug released into media over 18 hours. Culture of primary DCs with PHCCC liposomes reduced pro-inflammatory cytokine secretion while reducing toxicity four-fold compared with soluble PHCCC. During co-culture of DCs with myelin-reactive T cells from transgenic mice, PHCCC liposomes reduced T cell proliferation and interferon gamma secretion. These results support the potential of using liposomes to promote tolerance through biocompatible delivery of metabolic modulators. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2977-2985, 2017.

译文

:多发性硬化症(MS)是一种自身免疫性疾病,其中髓磷脂被错误地识别为异物并受到适应性免疫系统的攻击。树突状细胞(DC)通过向T细胞呈递抗原来指导适应性免疫,因此可作为自身免疫疗法的靶标。 N-苯基-7-(羟基亚氨基)环丙[b]铬n-1a-羧酰胺(PHCCC)是代谢型谷氨酸受体4(mGluR4)的正变构调节剂,可通过改变细胞因子分泌来促进T细胞调节,从而偏向T细胞分化。然而,PHCCC的治疗潜力受到剂量限制的毒性,不良的溶解性以及需要频繁给药的限制。我们假设PHCCC的脂质体递送可能使这种疏水性药物安全有效地递送,从而利用新陈代谢作为控制自身反应性免疫细胞中炎症的手段。 PHCCC容易封装在用聚乙二醇修饰的脂质体中。在水槽条件下,控释导致58%的药物在18小时内释放到培养基中。与可溶性PHCCC相比,用PHCCC脂质体培养初级DC可以减少促炎性细胞因子的分泌,同时将毒性降低四倍。在DC与来自转基因小鼠的髓磷脂反应性T细胞共培养期间,PHCCC脂质体降低了T细胞增殖和干扰素γ分泌。这些结果支持使用脂质体通过代谢调节剂的生物相容性递送来提高耐受性的潜力。分级为4 +©2017 Wiley Periodicals,Inc.J Biomed Mater Res Part A:105A:2977-2985,2017。

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