Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909
Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909
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DOI：
10.1172/jci200523373
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发表时间：
2005-03-01
影响因子：
15.9
通讯作者：
Romero, P
中科院分区：
文献类型：
--
作者：
Speiser, DE;Liénard, D;Romero, P
通过疫苗诱导有效的CD 8（+）T细胞应答以对抗微生物或肿瘤仍然是一个主要挑战，因为许多人类疫苗的候选物已被证明免疫原性差。脱氧胞苷-脱氧鸟苷寡脱氧核苷酸（CpG ODN）触发Toll样受体9，导致树突状细胞成熟，可以增强小鼠中基于肽的疫苗的免疫原性。我们测试了合成的ODN CpG 7909是否可以改善人肿瘤抗原特异性CD 8 + T细胞应答。8名HLA-A2（+）黑色素瘤患者接受4次每月一次的低剂量CpG 7909与黑色素瘤抗原A（Melan-A;与MART-1相同）类似肽和不完全弗氏佐剂混合疫苗接种。所有患者均表现出快速和强烈的抗原特异性T细胞应答：Melan-A特异性T细胞的频率达到循环CD 8（+）T细胞的3%以上。这比在8名类似治疗但没有CpG的对照患者中观察到的频率高一个数量级，并且比在先前使用合成疫苗的研究中观察到的高1-3个数量级。增强的T细胞群主要由效应记忆细胞组成，其部分分泌IFN-γ并在体外表达颗粒酶B和穿孔素。在体外，T细胞克隆识别并杀死黑色素瘤细胞在抗原特异性的方式。因此，CpG 7909是一种有效的疫苗佐剂，可促进人体内强烈的抗原特异性CD 8（+）T细胞应答。
The induction of potent CD8(+) T cell responses by vaccines to fight microbes or tumors remains a major challenge, as many candidates for human vaccines have proved to be poorly immunogenic. Deoxycytidyl-deoxyguanosin oligodeoxynucleotides (CpG ODNs) trigger Toll-like receptor 9, resulting in dendritic cell maturation that can enhance immunogenicity of peptide-based vaccines in mice. We tested whether a synthetic ODN, CpG 7909, could improve human tumor antigen-specific CD8+ T cell responses. Eight HLA-A2(+) melanoma patients received 4 monthly vaccinations of low-dose CpG 7909 mixed with melanoma antigen A (Melan-A; identical to MART-1) analog peptide and incomplete Freund's adjuvant. All patients exhibited rapid and strong antigen-specific T cell responses: the frequency of Melan-A-specific T cells reached over 3% of circulating CD8(+)T cells. This was one order of magnitude higher than the frequency seen in 8 control patients treated similarly but without CpG and 1-3 orders of magnitude higher than that seen in previous studies with synthetic vaccines. The enhanced T cell populations consisted primarily of effector memory cells, which in part secreted IFN-gamma and expressed granzyme B and perforin ex vivo. In vitro, T cell clones recognized and killed melanoma cells in an antigen-specific manner. Thus, CpG 7909 is an efficient vaccine adjuvant that promotes strong antigen-specific CD8(+) T cell responses in humans.