Mobilization of dendritic cell precursors into the circulation by administration of MIP-1alpha in mice.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Zhang
Yanyun
Y
Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo, Tokyo, Japan.
Yoneyama
Hiroyuki
H
Wang
Yong
Y
Ishikawa
Sho
S
Hashimoto
Shin-ichi
S
Gao
Ji-Liang
JL
Murphy
Philip
P
Matsushima
Kouji
K
D000818:Animals; D045744:Cell Line, Tumor; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods*; D019402:Macrophage Inflammatory Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000378:metabolism; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic
C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor