Nanoparticles for the induction of antigen-specific Tregs.
Nanoparticles for the induction of antigen-specific Tregs.
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DOI：
10.2217/imt.13.25
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发表时间：
2013-05
期刊：
影响因子：
2.8
通讯作者：
F. Quintana
中科院分区：
文献类型：
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作者：
F. Quintana
NPs扩增记忆样CD8+Tregs在非肥胖糖尿病(NOD)小鼠自发自身免疫性1型糖尿病的病程中，一群低亲和力的自身反应性CD8 T细胞获得一种调节性表型。为了扩展这些CD8Tregs，Santamaria和他的同事开发了包含与疾病相关的自肽和I类MHC(pMHC-NPs)复合体的NPs[4]。在糖尿病NOD小鼠和人源化NOD小鼠中，给予pMHC-NPs可消除糖尿病反应并恢复正常血糖[4]。机制研究表明，pMHC-NPs不被CD11b、CD11c或B细胞摄取，而是在体内靶向T细胞，导致类似CCR7CXCR3CD62LCD44CD122CD8的调节性记忆T细胞的扩张，这是一种不同于经典记忆T细胞的表型。PMHC-NPs诱导的CD8Tregs可产生干扰素-γ，但不能刺激细胞增殖或分泌IL-2。此外，这些CD8Tregs在体外和体内都显示出抑制活性，这是因为它们能够通过一种涉及干扰素-g、吲哚胺2，3-双加氧酶(IDO)和穿孔素的机制来杀伤APC。PMHC-NPs诱导的CD8Tregs抑制活性的一个重要特征是它们抑制不同抗原特异性的T细胞的激活。由于在自身免疫性疾病的过程中，几种自身抗原通常是靶标[5]，而每个患者自身免疫反应靶标的所有抗原的身份通常是未知的，这种旁观者抑制特雷格的专门群体控制着健康个体的活动。Treg缺陷通常与自身免疫性疾病的发生有关。因此，抗原特异性Tregs的扩增被认为是治疗自身免疫性疾病的一种潜在方法；然而，在体内或体外产生大量抗原特异性Tregs的方法仍然缺乏。纳米技术为扩大抗原特异性Tregs和治疗自身免疫性疾病提供了新的工具。本文讨论了利用纳米技术重建免疫耐受和治疗自身免疫性疾病的最新实例。自身免疫性疾病是由于免疫系统对自身抗原反应异常引起的。在健康个体中，免疫系统的活动由树突状细胞的专门种群控制[1]。然而，在患有自身免疫性疾病的患者中，通常会发现Treg缺陷。因此，抗原特异性Tregs的产生被认为是治疗自身免疫性疾病的一种有前途的方法，但在体内或体外产生大量抗原特异性Tregs的方法仍然缺乏。纳米颗粒(NPs)具有独特的物理和化学特性，这促使它们在医学上的应用。其中一些特征对药物输送领域特别有意义[3]：
Expansion of memory-like CD8+ Tregs with NPs During the course of spontaneous autoimmune Type 1 diabetes in nonobese diabetic (NOD) mice, a population of low-avidity self-reactive CD8 T cells acquires a regulatory phenotype. To expand these CD8 Tregs, Santamaria and coworkers developed NPs containing complexes of disease-relevant self-peptides and the class I MHC (pMHC-NPs)[4]. The administration of pMHC-NPs abrogated the diabetogenic response and restored normoglycemia in diabetic NOD mice, and also in humanized NOD mice [4]. Mechanistic studies determined that pMHC-NPs were not taken up by CD11b, CD11c or B cells, and instead targeted T cells in vivo, leading to the expansion of regulatory memory-like CCR7 CXCR3CD62LCD44CD122CD8 T cells, a phenotype that differs from that of ‘classical’ memory T cells. The CD8 Tregs induced by pMHC-NPs produced IFN-g, but did not proliferate or secrete IL-2 in response to stimulation. Moreover, these CD8 Tregs showed suppressive activity in vitro and in vivo, as a result of their ability to kill APCs through a mechanism that involved IFN-g, indoleamine 2,3-dioxygenase (IDO) and perforin. An important feature of the suppressive activity of the CD8 Tregs induced by pMHC-NPs is that they suppressed the activation of T cells of different antigen specificities. Since several self-antigens are usually targeted during the course of autoimmune diseases [5] and the identity of all the antigens targeted by the autoimmune response in each individual patient is usually unknown, this bystander suppression Specialized populations of Tregs control activity in healthy individuals. Treg deficits are usually associated with the development of auto immune diseases. Thus, the expansion of antigen-specific Tregs is viewed as a potential therapeutic approach for autoimmune disorders; however, methods for generating significant numbers of antigenspecific Tregs in vivo or in vitro are still missing. Nanotechnology offers new tools for the expansion of antigen-specific Tregs and the treatment of autoimmune disorders. This article discusses recent examples of the use of nano technologybased approaches to re-establish immune tolerance and treat autoimmune diseases. Autoimmune diseases result from the dysregulated reactivity of the immune system against self-antigens. In healthy individuals, the activity of the immune system is controlled by specialized populations of Tregs [1]. In patients afflicted by autoimmune diseases, however, Treg deficits are usually found [2]. Thus, the generation of antigen-specific Tregs is viewed as a promising approach for the treatment of autoimmune disorders, but methods for generating significant numbers of antigen-specific Tregs in vivo or in vitro are still missing. Nanoparticles (NPs) have unique physical and chemical features that prompted their use in medicine. Some of these features are of particular interest for the field of drug delivery [3]: