In vivo manipulation of dendritic cells to induce therapeutic immunity
In vivo manipulation of dendritic cells to induce therapeutic immunity
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DOI：
10.1182/blood.v99.5.1676
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发表时间：
2002-03-01
期刊：
影响因子：
20.3
通讯作者：
Fong, L
中科院分区：
文献类型：
--
作者：
Merad, M;Sugie, T;Fong, L
高效抗原呈递和t细胞启动是有效抗肿瘤免疫的重要组成部分。树突状细胞对这两种功能都至关重要，但迄今为止还没有设计出一种方法，既能将抗原靶向这些细胞，又能原位激活它们，从而诱导全身免疫。在这项研究中，我们将树突状细胞生长因子Flt3配体与树突状细胞激活剂、免疫刺激DNA和肿瘤抗原结合起来，在体内激活和加载树突状细胞。初步研究表明，免疫刺激DNA不仅能激活树突状细胞，还能延长其在体内和体外的存活时间。在用Flt3配体治疗小鼠后，免疫刺激DNA和抗原共同给药可诱导有效的抗肿瘤免疫，既可预防肿瘤，又可使已有肿瘤消退。肿瘤保护需要CD8细胞毒性T淋巴细胞，而不需要CD4 T细胞。自然杀伤细胞也有助于肿瘤保护。这些结果表明，树突状细胞可以在原位加载抗原并被激活，为树突状细胞靶向的临床策略提供了依据。
Efficient antigen presentation and T-cell priming are essential components of effective antitumor immunity. Dendritic cells are critical to both of these functions but to date no method has been devised that both targets antigen to these cells and activates them, in situ, in a manner that Induces systemic immunity. In this study we combined a dendritic cell growth factor, Flt3 ligand, with a dendritic cell activator, Immunostimulatory DNA, and a tumor antigen to activate and load dendritic cells in vivo. Initial studies showed that immunostimulatory DNA not only activates dendritic cells but also prolongs their survival in vivo and in vitro. Following treatment of mice with Flt3 ligand, coadministration of immunostimulatory DNA and antigen induced potent antitumor immunity, resulting in both tumor prevention and regression of existing tumors. CD8 cytotoxic T lymphocytes but not CD4 T cells were required for tumor protection. Natural killer cells also contributed to tumor protection. These results show that dendritic cells can be loaded with antigen and activated, in situ, and provide the basis for dendritic cell- targeted clinical strategies.