Zhang Yanyun, Yoneyama Hiroyuki, Wang Yong, Ishikawa Sho, Hashimoto Shin-ichi, Gao Ji-Liang, Murphy Philip, Matsushima Kouji
Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo, Tokyo, Japan.
J Natl Cancer Inst. 2004 Feb 4;96(3):201-9. doi: 10.1093/jnci/djh024.
Dendritic cells (DCs) play a central role in immune responses and may be useful adjuvants for tumor vaccine therapy. We previously reported that F4/80(-)B220(-)CD11c(+) DC precursors expressing the CC chemokine receptors CCR1 and CCR5 are mobilized rapidly into the circulation in mice injected with Propionibacterium acnes and are recruited into inflammatory tissue by macrophage inflammatory protein 1alpha (MIP-1alpha), which binds to CCR1 and CCR5. Here we investigate the mechanisms of DC precursor mobilization and the antitumor effect of these cells in mice.
Numbers of DC precursors in peripheral blood were determined in P. acnes-treated mice (groups of 10 C57BL/B6 [B6] wild-type mice, CCR1(-/-) mice, CCR5(-/-) mice, and B6 mice treated with antibody to MIP-1alpha or control antibody) and in B6 mice injected with recombinant MIP-1alpha. MIP-1alpha-mobilized DC precursors matured by treatment with granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor-alpha and pulsed with B16 melanoma lysates were assayed for their ability to confer protective immunity against tumor challenge in vivo and to induce cytotoxic T lymphocytes against B16 tumor cells in vitro.
The recruitment of DC precursors into the circulation by P. acnes administration was higher in B6 mice (12.6%, 95% confidence interval [CI] = 9.1% to 16.1%) than in CCR1(-/-) (9.0%, 95% CI = 7.5% to 10.5%), CCR5(-/-) (6.3%, 95% CI = 5.2% to 7.3%), or anti-MIP-1alpha antibody-treated (6.6%, 95% CI = 5.7% to 7.5%) mice. Injection of MIP-1alpha also mobilized DC precursors into the circulation (13.1%, 95% CI = 10.8% to 15.6%). Matured MIP-1alpha-mobilized-DC precursors pulsed with B16 tumor lysates elicited B16-specific antitumor immunity in vitro and in vivo.
MIP-1alpha and its receptors are important in recruiting DC precursors into the circulation. DC precursors mobilized rapidly by MIP-1alpha may provide sufficient useful DC precursors for DC-based vaccination in cancer treatment.
树突状细胞（DCs）在免疫反应中起核心作用，可能是肿瘤疫苗治疗的有用佐剂。我们之前报道过，表达CC趋化因子受体CCR1和CCR5的F4/80(-)B220(-)CD11c(+)DC前体细胞在注射痤疮丙酸杆菌的小鼠中迅速动员到循环中，并被与CCR1和CCR5结合的巨噬细胞炎性蛋白1α（MIP-1α）招募到炎症组织中。在此，我们研究DC前体细胞动员的机制以及这些细胞在小鼠中的抗肿瘤作用。
在痤疮丙酸杆菌处理的小鼠（每组10只C57BL/B6 [B6]野生型小鼠、CCR1(-/-)小鼠、CCR5(-/-)小鼠以及用抗MIP-1α抗体或对照抗体处理的B6小鼠）和注射重组MIP-1α的B6小鼠中测定外周血中DC前体细胞的数量。用粒细胞-巨噬细胞集落刺激因子、白细胞介素4和肿瘤坏死因子-α处理并脉冲加载B16黑色素瘤裂解物使MIP-1α动员的DC前体细胞成熟，检测其在体内赋予针对肿瘤攻击的保护性免疫以及在体外诱导针对B16肿瘤细胞的细胞毒性T淋巴细胞的能力。
B6小鼠中通过给予痤疮丙酸杆菌将DC前体细胞募集到循环中的比例（12.6%，95%置信区间[CI]=9.1%至16.1%）高于CCR1(-/-)小鼠（9.0%，95%CI=7.5%至10.5%）、CCR5(-/-)小鼠（6.3%，95%CI=5.2%至7.3%）或抗MIP-1α抗体处理的小鼠（6.6%，95%CI=5.7%至7.5%）。注射MIP-1α也能将DC前体细胞动员到循环中（13.1%，95%CI=10.8%至15.6%）。用B16肿瘤裂解物脉冲加载的成熟的MIP-1α动员的DC前体细胞在体外和体内引发了B16特异性抗肿瘤免疫。
MIP-1α及其受体在将DC前体细胞募集到循环中起重要作用。由MIP-1α快速动员的DC前体细胞可能为癌症治疗中基于DC的疫苗接种提供足够有用的DC前体细胞。
