工程化人类树突状细胞外泌体作为免疫调节的有效递送系统。
Engineered Human Dendritic Cell Exosomes as Effective Delivery System for Immune Modulation.
机构信息
Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA.
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
出版信息
Int J Mol Sci. 2023 Jul 11;24(14):11306. doi: 10.3390/ijms241411306.
Exosomes (exos) contain molecular cargo of therapeutic and diagnostic value for cancers and other inflammatory diseases, but their therapeutic potential for periodontitis (PD) remains unclear. Dendritic cells (DCs) are the directors of immune response and have been extensively used in immune therapy. We previously reported in a mouse model of PD that custom murine DC-derived exo subtypes could reprogram the immune response toward a bone-sparing or bone-loss phenotype, depending on immune profile. Further advancement of this technology requires the testing of human DC-based exos with human target cells. Our main objective in this study is to test the hypothesis that human monocyte-derived dendritic cell (MoDC)-derived exos constitute a well-tolerated and effective immune therapeutic approach to modulate human target DC and T cell immune responses in vitro. MoDC subtypes were generated with TGFb/IL-10 (regulatory (reg) MoDCs, CD86HLA-DRPDL1), LPS (stimulatory (stim) MoDCs, CD86HLA-DRPDL1) and buffer (immature (i) MoDCs, CD86HLA-DRPDL1). Exosomes were isolated from different MoDC subtypes and characterized. Once released from the secreting cell into the surrounding environment, exosomes protect their prepackaged molecular cargo and deliver it to bystander cells. This modulates the functions of these cells, depending on the cargo content. RegMoDCexos were internalized by recipient MoDCs and induced upregulation of PDL1 and downregulation of costimulatory molecules CD86, HLADR, and CD80, while stimMoDCexos had the opposite influence. RegMoDCexos induced CD25+Foxp3+ Tregs, which expressed CTLA4 and PD1 but not IL-17A. In contrast, T cells treated with stimMoDCexos induced IL-17A+ Th17 T cells, which were negative for immunoregulatory CTLA4 and PD1. T cells and DCs treated with iMoDCexos were immune 'neutral', equivalent to controls. In conclusion, human DC exos present an effective delivery system to modulate human DC and T cell immune responses in vitro. Thus, MoDC exos may present a viable immunotherapeutic agent for modulating immune response in the gingival tissue to inhibit bone loss in periodontal disease.
外泌体（exos）包含具有治疗和诊断价值的分子货物，可用于癌症和其他炎症性疾病，但它们在牙周炎（PD）中的治疗潜力尚不清楚。树突状细胞（DCs）是免疫反应的指导者，已广泛用于免疫治疗。我们之前在 PD 的小鼠模型中报告说，根据免疫特征，定制的鼠源性 DC 衍生的外泌体亚型可以重新编程免疫反应，使其偏向于骨保护或骨丢失表型。这项技术的进一步发展需要用人类靶细胞测试基于人类 DC 的外泌体。我们在这项研究中的主要目的是检验以下假设，即人类单核细胞衍生的树突状细胞（MoDC）衍生的外泌体构成一种耐受良好且有效的免疫治疗方法，可以调节体外人类靶 DC 和 T 细胞的免疫反应。用 TGFb/IL-10（调节性（reg）MoDCs，CD86HLA-DRPDL1）、LPS（刺激性（stim）MoDCs，CD86HLA-DRPDL1）和缓冲液（未成熟（i）MoDCs，CD86HLA-DRPDL1）生成 MoDC 亚型。从不同的 MoDC 亚型中分离出外泌体并进行表征。外泌体一旦从分泌细胞释放到周围环境中，就会保护其预先包装的分子货物，并将其递送至旁观者细胞。这取决于货物内容而调节这些细胞的功能。RegMoDCexos 被受体 MoDC 内化，并诱导 PD-L1 上调和共刺激分子 CD86、HLADR 和 CD80 下调，而 stimMoDCexos 则产生相反的影响。RegMoDCexos 诱导 CD25+Foxp3+Tregs，其表达 CTLA4 和 PD1，但不表达 IL-17A。相比之下，用 stimMoDCexos 处理的 T 细胞诱导产生 IL-17A+Th17 T 细胞，这些细胞对免疫调节 CTLA4 和 PD1 呈阴性。用 iMoDCexos 处理的 T 细胞和 DC 呈免疫“中性”，与对照相当。总之，人源性 DC 外泌体提供了一种有效的递药系统，可在体外调节人源性 DC 和 T 细胞的免疫反应。因此，MoDC 外泌体可能成为一种可行的免疫治疗药物，用于调节牙龈组织中的免疫反应，以抑制牙周病中的骨质流失。
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