title: Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages.
abstract: Activation of macrophages is a prerequisite for their antitumor effects. Several reagents, including agonistic anti-CD40 monoclonal antibody (anti-CD40), CpG oligodeoxynucleotides (CpG) and monophosphoryl lipid A (MPL), can stimulate activation of macrophages. Our previous studies showed synergy between anti-CD40 and CpG and between anti-CD40 and MPL in macrophage activation and antitumor efficacy in mice. In the present study, we asked whether there was synergy among these three reagents. The activation of adherent peritoneal exudate cells (PEC) obtained from mice injected with anti-CD40 and then treated with CpG and/or MPL in vitro was determined by their ability to suppress proliferation of tumor cells and to produce various cytokines and chemokines in vitro. Cell sorting and histology followed by functional testing showed that macrophages were the main cell population in PEC activated by CD40 ligation in vivo. A combination of anti-CD40, CpG or MPL activated PEC to suppress proliferation of B16 cells and produce nitric oxide far greater than the single reagents or any of the double combinations of these reagents. In addition, the combination of all three reagents activated PEC to secrete IL-12, IFN-γ and MCP-1 to a greater degree than any single reagent or any two combined reagents. These results demonstrate that macrophages can be synergistically activated by anti-CD40, CpG and MPL, suggesting that this novel combined approach might be further investigated as potential cancer therapy.
authors.affiliation: Institute of Immunology, Shandong University School of Medicine, Jinan, China; University of Wisconsin, Department of Human Oncology, Madison, WI, USA.
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: University of Wisconsin, Department of Obstetrics and Gynecology, Madison, WI, USA.
authors.forename: Mildred A R
authors.initials: MA
authors.lastname: Felder
authors.affiliation: University of Wisconsin, Department of Human Oncology, Madison, WI, USA; University of Wisconsin, Department of Pediatrics, Madison, WI, USA; University of Wisconsin, Paul P. Carbone Comprehensive Cancer Center, Madison, WI, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
authors.affiliation: University of Wisconsin, Department of Human Oncology, Madison, WI, USA; University of Wisconsin, Paul P. Carbone Comprehensive Cancer Center, Madison, WI, USA. Electronic address: rakhmil@humonc.wisc.edu.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D019013:CD40 Antigens / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D061251:Primary Cell Culture; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D004338:Drug Combinations; D008050:Lipid A; D009838:Oligodeoxyribonucleotides; C048436:monophosphoryl lipid A
keywords: Anti-CD40; CpG; Immunotherapy; Macrophages; Monophosphoryl lipid A
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