title: The imidazoquinolines, imiquimod and R-848, induce functional, but not phenotypic, maturation of human epidermal Langerhans' cells.
abstract: Imiquimod (R-837) and its more potent derivative (R-848) are imidazoquinolines that have adjuvant activity in cultured human mononuclear cells. Its mechanism of action on epidermal antigen-presenting cells is not known. The purpose of the present investigation was to determine whether imiquimod and R-848 affect human epidermal Langerhans' cells' (LC) in vitro maturation. Pulse incubations (6-16 h) of cultured unfractionated epidermal cells or highly enriched LC suspensions with either imiquimod or R-848 (0. 05-5.0 microg/ml of culture medium) reproducibly enhanced their ability to induce T-cell proliferation in a primary mixed lymphocyte reaction. There was a 30 to 300% increase in T-lymphocyte proliferation induced by either imiquimod- or R-848-treated LC when compared to control, untreated LC. IFN-gamma secretion by T-lymphocytes stimulated by imiquimod- or R-848-treated LC was increased compared to control, untreated LC. After a 6-h incubation, phenotypic analysis of control-, imiquimod-, or R-848-treated LC indicated that such antigen-presenting cells were in an "intermediate" state of maturation (CD1a(+), HLA-DR, DP, DQ(bright+), CD40(low+), CD86(high+), and CD80(low+)). RNase protection assays demonstrated that either imiquimod or R-848 treatments increased steady-state transcripts encoding for IL-12 p40, IL-1beta, TNF-alpha, and IL-1 receptor antagonist by LC. These data indicate that imiquimod and R-848 dissociate the functional maturation (cytokine-mediated) and phenotypic maturation of epidermal LC. These data warrant further exploration for the use of imidazoquinoline-treated LC or other DC subsets for processing and presentation of viral peptides to Th-lymphocytes as a novel vaccine strategy to induce protective antiviral responses.
authors.affiliation: Department of Dermatology, 3M Pharmaceuticals, St. Paul, Minnesota, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Burns
authors.forename: B
authors.initials: B
authors.lastname: Ferbel
authors.forename: M
authors.initials: M
authors.lastname: Tomai
authors.forename: R
authors.initials: R
authors.lastname: Miller
authors.forename: A A
authors.initials: AA
authors.lastname: Gaspari
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000634:Aminoquinolines / Q000494:pharmacology*; D017951:Antigen Presentation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000077271:Imiquimod; D007155:Immunologic Factors / Q000494:pharmacology*; D007801:Langerhans Cells / Q000166:cytology*; D007959:Lymphocyte Culture Test, Mixed; D010641:Phenotype; D018417:Th1 Cells / Q000166:cytology
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D016207:Cytokines; D007093:Imidazoles; D007155:Immunologic Factors; D000077271:Imiquimod; C402365:resiquimod