PD-L1-and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease
PD-L1-and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease
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DOI：
10.1172/jci.insight.126025
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发表时间：
2019-09-19
期刊：
影响因子：
8
通讯作者：
Thomas, Ranjeny
中科院分区：
文献类型：
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作者：
Galea, Ryan;Nel, Hendrik J.;Thomas, Ranjeny
由MHC-II类限制性自身抗原特异性T细胞免疫引起的自身免疫性疾病包括全身炎性自身免疫性疾病、类风湿性关节炎和血管炎。虽然目前使用广效免疫抑制药物治疗，但更好的策略是通过利用DC抗原提呈来调节抗原特异性效应T细胞(TEFs)以恢复耐受性。我们使用包裹1α，25-二羟基维生素D3(骨化三醇)和抗原肽的脂质体靶向引流淋巴结(DLN)吞噬细胞的DC，以阐明DC和应答T细胞在静息和免疫条件下的耐受机制。与未免疫的小鼠相比，免疫小鼠的DLN中PD-L1的表达上调。皮下注射包裹OVA(323-339)和骨化三醇的脂质体，靶向免疫小鼠的DLN PD-L1(Hi)树突状细胞，并降低其MHC-II类表达。OVA(323)(-3)(39)/骨化三醇脂质体抑制T细胞的扩增、分化和功能，并以抗原特异性的方式诱导Foxp3(+)和IL-10(+)外周血树突状细胞，其依赖于PD-L1。多肽/骨化三醇脂质体在体外可调节人DC表达CD40并促进Treg的诱导。包裹骨化三醇和疾病相关肽的脂质体通过抑制抗原特异性记忆7细胞的分化和功能来抑制类风湿性关节炎和古德帕斯普雷血管炎模型的严重程度。相应地。多肽/骨化三醇脂质体利用DC PD-L1调节抗原特异性T细胞，并在炎症性自身免疫性疾病中诱导抗原特异性耐受。
Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1 alpha.,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA(323-339) and calcitriol targeted dLN PD-L1(hi) DCs of immunized mice and reduced their MHC class II expression. OVA(323)(-3)(39)/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3(+) and IL-10(+) peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory 7 cell differentiation and function. Accordingly. peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.