A new synthetic toll-like receptor 1/2 ligand is an efficient adjuvant for peptide vaccination in a human volunteer
A new synthetic toll-like receptor 1/2 ligand is an efficient adjuvant for peptide vaccination in a human volunteer
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DOI：
10.1186/s40425-019-0796-5
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发表时间：
2019-11-15
影响因子：
10.9
通讯作者：
Loeffler, Markus W.
中科院分区：
文献类型：
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作者：
Rammensee, Hans-Georg;Wiesmueller, Karl-Heinz;Loeffler, Markus W.
背景我们以前发现，细菌脂肽Pam（3）Cys-Ser-Ser，同时作为toll样受体（TLR）1/2配体，当与合成肽共价偶联时，在小鼠中作为诱导病毒特异性CD 8（+）T细胞的强佐剂。我们现在设计了一种新的水溶性合成Pam（3）Cys衍生物，命名为XS 15，并通过TLR 2 NF-κ B荧光素酶报告基因测定对其进行体外表征。此外，通过流式细胞术以及使用免疫测定的细胞因子诱导来评估XS 15通过6-磺基LacNAc（+）单核细胞活化免疫细胞和刺激肽特异性CD 8（+）T和NK细胞的能力。通过ELISpot测定和免疫部位外周血细胞和浸润细胞的流式细胞术，以及免疫组织化学和成像，评估志愿者接种病毒肽后功能性免疫应答的诱导。在单次注射与油包水乳液（Montanide（TM）ISA 51 VG）中的未偶联肽混合的XS 15后，XS 15在人类志愿者中诱导强烈的离体CD 8（+）和T（H）1 CD 4（+）应答。注射部位局部形成的肉芽肿，含有高度活化的功能性CD 4（+）和CD 8（+）效应记忆T细胞。通过实验评估了疫苗肽特异性功能性T细胞的总数，估计肉芽肿中为3.0 x 10（5），外周血中为20.5 x 10（6）。因此，在一名志愿者中，我们显示了由肽与油包水乳剂中的有效佐剂组合形成的肉芽肿，仅在一次单次接种后，诱导在循环中和接种部位可检测到的抗原特异性T细胞。外周血中的离体T细胞应答可检测超过一年，并且可通过第二次接种强烈增强。因此，XS 15是用于肽疫苗接种，特别是用于个性化环境中的肿瘤肽疫苗的有希望的候选佐剂。
Background We previously showed that the bacterial lipopeptide Pam(3)Cys-Ser-Ser, meanwhile established as a toll-like receptor (TLR) 1/2 ligand, acts as a strong adjuvant for the induction of virus specific CD8(+) T cells in mice, when covalently coupled to a synthetic peptide. Case presentation We now designed a new water-soluble synthetic Pam(3)Cys-derivative, named XS15 and characterized it in vitro by a TLR2 NF-kappa B luciferase reporter assay. Further, the capacity of XS15 to activate immune cells and stimulate peptide-specific CD8(+) T and NK cells by 6-sulfo LacNAc(+) monocytes was assessed by flow cytometry as well as cytokine induction using immunoassays. The induction of a functional immune response after vaccination of a volunteer with viral peptides was assessed by ELISpot assay and flow cytometry in peripheral blood cells and infiltrating cells at the vaccination site, as well as by immunohistochemistry and imaging. XS15 induced strong ex vivo CD8(+) and T(H)1 CD4(+) responses in a human volunteer upon a single injection of XS15 mixed to uncoupled peptides in a water-in-oil emulsion (Montanide (TM) ISA51 VG). A granuloma formed locally at the injection site containing highly activated functional CD4(+) and CD8(+) effector memory T cells. The total number of vaccine peptide-specific functional T cells was experimentally assessed and estimated to be 3.0 x 10(5) in the granuloma and 20.5 x 10(6) in peripheral blood. Conclusion Thus, in one volunteer we show a granuloma forming by peptides combined with an efficient adjuvant in a water-in-oil-emulsion, inducing antigen specific T cells detectable in circulation and at the vaccination site, after one single vaccination only. The ex vivo T cell responses in peripheral blood were detectable for more than one year and could be strongly boosted by a second vaccination. Hence, XS15 is a promising adjuvant candidate for peptide vaccination, in particular for tumor peptide vaccines in a personalized setting.