Human innate responses and adjuvant activity of TLR ligands in vivo in mice reconstituted with a human immune system

人性化鼠标 免疫系统 免疫学 先天免疫系统 佐剂 体内 生物 趋化因子 CpG寡核苷酸 树突状细胞 CD8型 浆细胞样树突状细胞 DNA甲基化 生物技术 基因表达 基因 生物化学
作者
Liang Cheng,Zheng Zhang,Guangming Li,Feng Li,Li Wang,Liguo Zhang,Sandra Zurawski,Gérard Zurawski,Yves Lévy,Lishan Su
出处
期刊:Vaccine [Elsevier]
卷期号:35 (45): 6143-6153 被引量:42
标识
DOI:10.1016/j.vaccine.2017.09.052
摘要

TLR ligands (TLR-Ls) represent a class of novel vaccine adjuvants. However, their immunologic effects in humans remain poorly defined in vivo. Using a humanized mouse model with a functional human immune system, we investigated how different TLR-Ls stimulated human innate immune response in vivo and their applications as vaccine adjuvants for enhancing human cellular immune response. We found that splenocytes from humanized mice showed identical responses to various TLR-Ls as human PBMCs in vitro. To our surprise, various TLR-Ls stimulated human cytokines and chemokines differently in vivo compared to that in vitro. For example, CpG-A was most efficient to induce IFN-α production in vitro. In contrast, CpG-B, R848 and Poly I:C stimulated much more IFN-α than CpG-A in vivo. Importantly, the human innate immune response to specific TLR-Ls in humanized mice was different from that reported in C57BL/6 mice, but similar to that reported in nonhuman primates. Furthermore, we found that different TLR-Ls distinctively activated and mobilized human plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs) and monocytes in different organs. Finally, we showed that, as adjuvants, CpG-B, R848 and Poly I:C can all enhance antigen specific CD4+ T cell response, while only R848 and Poly I:C induced CD8+ cytotoxic T cells response to a CD40-targeting HIV vaccine in humanized mice, correlated with their ability to activate human mDCs but not pDCs. We conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans.
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