A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease.
A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease.
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DOI：
10.1021/nn405033r
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发表时间：
2014-03-25
期刊：
影响因子：
17.1
通讯作者：
Miller SD
中科院分区：
文献类型：
--
作者：
Hunter Z;McCarthy DP;Yap WT;Harp CT;Getts DR;Shea LD;Miller SD
靶向免疫耐受是治疗多种自身免疫性疾病的一种令人垂涎的治疗方法，因为目前的治疗方案通常涉及非特异性免疫抑制。使用乙烯碳二酰亚胺（ECDI）静脉（iv）输注与肽或蛋白自身抗原连接的凋亡同基因脾细胞已被证明是诱导外周抗原特异性耐受治疗自身免疫性疾病的有效方法。在这里，我们展示了可生物降解的聚乳酸-羟基乙酸（PLG）纳米颗粒作为一种安全、经济、高效的替代细胞载体诱导抗原特异性T细胞耐受的能力。我们描述了耐受性PLG颗粒的配方，并证明髓磷脂抗原偶联颗粒的管理可以预防和治疗复发-缓解性实验性自身免疫性脑脊髓炎（R-EAE），这是一种CD4 T细胞介导的多发性硬化症（MS）小鼠模型。经过表面活性剂修饰的现场制备的PLG颗粒在偶联肽和预防疾病诱导方面的功效超过了市售颗粒。最重要的是，髓磷脂抗原偶联的PLG纳米颗粒在急性疾病发病或高峰时施用时，能够显著改善正在进行的疾病和随后的复发，并在疾病缓解期间施用时最大限度地减少表位扩散。治疗性治疗可显著降低致脑Th1 （IFN-γ）和Th17 （IL-17a）细胞以及炎性单核/巨噬细胞的中枢神经系统浸润。总之，这些数据描述了一个抗原展示平台，它是安全的，低成本的，并且在诱导抗原特异性T细胞耐受方面非常有效。这样一个平台的发展对各种免疫介导疾病的治疗具有广泛的意义。
Targeted immune tolerance is a coveted therapy for the treatment of a variety of autoimmune diseases, as current treatment options often involve nonspecific immunosuppression. Intravenous (iv) infusion of apoptotic syngeneic splenocytes linked with peptide or protein autoantigens using ethylene carbodiimide (ECDI) has been demonstrated to be an effective method for inducing peripheral, antigen-specific tolerance for treatment of autoimmune disease. Here, we show the ability of biodegradable poly(lactic-co-glycolic acid) (PLG) nanoparticles to function as a safe, cost-effective, and highly efficient alternative to cellular carriers for the induction of antigen-specific T cell tolerance. We describe the formulation of tolerogenic PLG particles and demonstrate that administration of myelin antigen-coupled particles both prevented and treated relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a CD4 T cell-mediated mouse model of multiple sclerosis (MS). PLG particles made on-site with surfactant modifications surpass the efficacy of commercially available particles in their ability to couple peptide and to prevent disease induction. Most importantly, myelin antigen-coupled PLG nanoparticles are able to significantly ameliorate ongoing disease and subsequent relapses when administered at onset or at peak of acute disease, and minimize epitope spreading when administered during disease remission. Therapeutic treatment results in significantly reduced CNS infiltration of encephalitogenic Th1 (IFN-γ) and Th17 (IL-17a) cells as well as inflammatory monocytes/macrophages. Together, these data describe a platform for antigen display that is safe, low-cost, and highly effective at inducing antigen-specific T cell tolerance. The development of such a platform carries broad implications for the treatment of a variety of immune-mediated diseases.