title: Dendritic cell (DC)-based protection against an intracellular pathogen is dependent upon DC-derived IL-12 and can be induced by molecularly defined antigens.
abstract: Upon loading with microbial Ag and adoptive transfer, dendritic cells (DC) are able to induce immunity to infections. This offers encouragement for the development of DC-based vaccination strategies. However, the mechanisms underlying the adjuvant effect of DC are not fully understood, and there is a need to identify Ag with which to arm DC. In the present study, we analyzed the role of DC-derived IL-12 in the induction of resistance to Leishmania major, and we evaluated the protective efficacy of DC loaded with individual Leishmania Ag. Using Ag-pulsed Langerhans cells (LC) from IL-12-deficient or wild-type mice for immunization of susceptible animals, we showed that the inability to release IL-12 completely abrogated the capacity of LC to mediate protection against leishmaniasis. This suggests that the availability of donor LC-derived IL-12 is a requirement for the development of protective immunity. In addition, we tested the protective effect of LC loaded with Leishmania homolog of receptor for activated C kinase, gp63, promastigote surface Ag, kinetoplastid membrane protein-11, or Leishmania homolog of eukaryotic ribosomal elongation and initiation factor 4a. The results show that mice vaccinated with LC that had been pulsed with selected molecularly defined parasite proteins are capable of controlling infection with L. major. Moreover, the protective potential of DC pulsed with a given Leishmania Ag correlated with the level of their IL-12 expression. Analysis of the cytokine profile of mice after DC-based vaccination revealed that protection was associated with a shift toward a Th1-type response. Together, these findings emphasize the critical role of IL-12 produced by the sensitizing DC and suggest that the development of a DC-based subunit vaccine is feasible.
authors.affiliation: Institute for Molecular Biology of Infectious Diseases, University of Würzburg, Würzburg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Berberich
authors.forename: José R
authors.initials: JR
authors.lastname: Ramírez-Pineda
authors.forename: Christine
authors.initials: C
authors.lastname: Hambrecht
authors.forename: Gottfried
authors.initials: G
authors.lastname: Alber
authors.forename: Yasir A W
authors.initials: YA
authors.lastname: Skeiky
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology* / Q000637:transplantation; D005260:Female; D006790:Host-Parasite Interactions / Q000276:immunology; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007424:Intracellular Fluid / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D007801:Langerhans Cells / Q000276:immunology / Q000469:parasitology / Q000637:transplantation; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000276:immunology / Q000627:therapeutic use; D008666:Metalloendopeptidases / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010448:Peptide Initiation Factors / Q000276:immunology / Q000627:therapeutic use; D015800:Protozoan Proteins / Q000276:immunology / Q000627:therapeutic use; D016052:Protozoan Vaccines / Q000276:immunology / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; D016207:Cytokines; C092810:LeIF protein, Leishmania; D008562:Membrane Glycoproteins; D010448:Peptide Initiation Factors; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; C090009:kinetoplastid membrane protein 11, Leishmania donovani; C093139:LACK antigen, Leishmania; D018664:Interleukin-12; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania