Expanding antigen-specific regulatory networks to treat autoimmunity
Expanding antigen-specific regulatory networks to treat autoimmunity
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DOI：
10.1038/nature16962
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发表时间：
2016-02-25
期刊：
影响因子：
64.8
通讯作者：
Santamaria, Pere
中科院分区：
文献类型：
--
作者：
Clemente-Casares, Xavier;Blanco, Jesus;Santamaria, Pere
调节性T细胞有望作为自身免疫性治疗干预的靶点，但目前还没有能够在体内扩增抗原特异性调节性T细胞的方法。在这里，我们表明，全身递送与自身免疫疾病相关肽结合的纳米颗粒与主要组织相容性复合物II类（pMHCII）分子触发抗原特异性调节CD4（+）T细胞1型（T（R）1）样细胞在不同的小鼠模型中的产生和扩增，包括小鼠人源化与患者的淋巴细胞，导致建立的自身免疫现象的解决。10种基于pMHCII的纳米药物显示出相似的生物学效应，无论遗传背景、同源T细胞群体的流行率或MHC限制如何。这些纳米药物促进疾病引发的自身反应性T细胞分化为T（R）1样细胞，T（R）1样细胞又抑制自身抗原负载的抗原呈递细胞，并驱动同源B细胞分化为疾病抑制调节性B细胞，而不损害全身免疫。因此，基于pMHCII的纳米药物代表了一类新的药物，可能用于以疾病特异性方式治疗广谱自身免疫性疾病。
Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (T(R)1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into T(R)1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.