title: Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation.
abstract: A key and limiting step in the process of generating human monocyte-derived dendritic cells (DC) for clinical applications is maturation. In the setting of immunotherapy, DC are matured ex vivo by culturing them with various agents that mimic the conditions encountered at a site of inflammation. This study examined whether the ex vivo DC maturation step could be replaced by maturing DC in situ by injecting immature DC into sites pre-exposed to agents that induce a microenvironment conducive to in situ maturation of the injected DC. The hypothesis was that recapitulation of the physiological conditions occurring during pathogen infection would lead to optimal conditions for DC maturation, migration, and function. Murine immature DC injected into adjuvant (Adjuprime, poly-arginine, or Imiquimod)-pretreated skin exhibited lymph node migratory capacity comparable to and immunostimulatory capacity equal to or exceeding that of ex vivo matured DC. Acquisition of migratory capacity did not always correlate with enhanced immunostimulatory capacity. Immunostimulatory capacity was not enhanced when mature DC were injected into adjuvant-pretreated sites and remained below that seen with immature DC matured in situ. Immature DC injected into adjuvant-pretreated sites were more effective than mature DC in stimulating antitumor immunity in mice. (111)Indium-labeled human monocyte-derived immature DC injected into adjuvant (Imiquimod)-pretreated sites in cancer patients acquired lymph node migratory capacity comparable to ex vivo matured DC. This study shows that in situ maturation offers a simpler and potentially superior method to generate potent immunostimulatory DC for clinical immunotherapy.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Nair
authors.forename: Catherine
authors.initials: C
authors.lastname: McLaughlin
authors.forename: Alon
authors.initials: A
authors.lastname: Weizer
authors.forename: Zhen
authors.initials: Z
authors.lastname: Su
authors.forename: David
authors.initials: D
authors.lastname: Boczkowski
authors.forename: Jens
authors.initials: J
authors.lastname: Dannull
authors.forename: Johannes
authors.initials: J
authors.lastname: Vieweg
authors.forename: Eli
authors.initials: E
authors.lastname: Gilboa
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology*; D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000637:transplantation*; D006801:Humans; D000077271:Imiquimod; D007279:Injections, Subcutaneous; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D012867:Skin / Q000166:cytology* / Q000276:immunology*; D013045:Species Specificity; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D000077271:Imiquimod