Controlled delivery of a metabolic modulator promotes regulatory T cells and restrains autoimmunity
Controlled delivery of a metabolic modulator promotes regulatory T cells and restrains autoimmunity
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DOI：
10.1016/j.jconrel.2015.05.277
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发表时间：
2015-07-28
影响因子：
10.8
通讯作者：
Jewell, Christopher M.
中科院分区：
文献类型：
--
作者：
Gammon, Joshua M.;Tostanoski, Lisa H.;Jewell, Christopher M.
当免疫系统异常识别和攻击自身分子时，发生自身免疫疾病。树突状细胞（Dendritic cells，DCs）在启动适应性免疫应答中起重要作用，是近年来自体免疫治疗的新靶点。N-苯基-7-（羟亚氨基）环丙烯[ B]色烯-1a-甲酰胺（PHCCC）是一种小分子谷氨酸受体增强剂，它改变了DC代谢谷氨酸的方式，从而使细胞因子分泌倾斜以偏向T细胞功能。当小鼠每天接受PHCCC全身注射时，这些作用通过使T细胞远离炎性T（H）17细胞并朝向调节性T细胞（T-REG）极化而在多发性硬化症（MS）小鼠模型中提供保护。然而，需要频繁、持续的治疗来产生和维持治疗益处。因此，PHCCC的使用受到溶解度差、需要频繁给药和细胞毒性的限制。我们假设，从可降解纳米颗粒（NP）中控制释放PHCCC可能会通过改变DC功能来解决这些挑战，以降低治疗频率和毒性来维持疗效。这一想法可以作为一种新的策略，利用生物材料通过代谢调节剂的控制输送来增强免疫功能。PHCCC很容易封装在纳米颗粒中，在三天内控制释放89%的药物到介质中。原代DC或DC和T细胞与PHCCC NP共培养物的培养减少了DC活化和促炎细胞因子的分泌，同时使T细胞远离T（H）17并朝向T-REG表型转移。重要的是，与可溶性PHCCC相比，在NP中递送至细胞的PHCCC的毒性低36倍。与以相同剂量和频率用可溶性药物治疗的小鼠相比，每三天用PHCCC NP治疗的小鼠延迟了疾病发作并降低了疾病严重程度。这些结果突出了通过控制递送代谢调节剂来促进耐受性的潜力，所述代谢调节剂改变DC信号传导至CD 3 T细胞，并且表明未来可以通过提供更长期释放的工程材料来实现的收益。(C)2015年，作者。由爱思唯尔公司出版
Autoimmune disorders occur when the immune system abnormally recognizes and attacks self-molecules. Dendritic cells (DCs) play a powerful role in initiating adaptive immune response, and are therefore a recent target for autoimmune therapies. N-Phenyl-7-(hydroxyimino) cyclopropa[ b] chromen-1a-carboxamide (PHCCC), a small molecule glutamate receptor enhancer, alters how DCs metabolize glutamate, skewing cytokine secretion to bias T cell function. These effects provide protection in mouse models of multiple sclerosis (MS) by polarizing T cells away from inflammatory T(H)17 cells and toward regulatory T cells (T-REG) when mice receive daily systemic injections of PHCCC. However, frequent, continued treatment is required to generate and maintain therapeutic benefits. Thus, the use of PHCCC is limited by poor solubility, the need for frequent dosing, and cell toxicity. We hypothesized that controlled release of PHCCC from degradable nanoparticles (NPs) might address these challenges by altering DC function to maintain efficacy with reduced treatment frequency and toxicity. This idea could serve as a new strategy for harnessing biomaterials to polarize immune function through controlled delivery of metabolic modulators. PHCCC was readily encapsulated in nanoparticles, with controlled release of 89% of drug into media over three days. Culture of primary DCs or DC and T cell co-cultures with PHCCC NPs reduced DC activation and secretion of pro-inflammatory cytokines, while shifting T cells away from T(H)17 and toward T-REG phenotypes. Importantly, PHCCC delivered to cells in NPs was 36-fold less toxic compared with soluble PHCCC. Treatment of mice with PHCCC NPs every three days delayed disease onset and decreased disease severity compared with mice treated with soluble drug at the same dose and frequency. These results highlight the potential to promote tolerance through controlled delivery of metabolic modulators that alter DC signaling to polarize T cells, and suggest future gains that could be realized by engineering materials that provide longer term release. (C) 2015 The Authors. Published by Elsevier B.V.