Dendritic cells matured with TNF can be further activated in vitro and after subcutaneous injection in vivo which converts their tolerogenicity into immunogenicity

J Immunother. Jul-Aug 2006;29(4):407-15. doi: 10.1097/01.cji.0000210081.60178.b4.

Abstract

Dendritic cell (DC) maturation can occur by different types of stimuli. Previously, we described that murine DC matured with tumor necrosis factor (TNF) up-regulate surface MHC and costimulatory molecules but lack cytokine release, and therefore termed them semi-mature DC. These TNF/DC-induced tolerance after intravenous (i.v.) injection in a model of experimental autoimmune encephalomyelitis (EAE). Here, we show that TNF/DC are not terminally differentiated but can still respond to the microbial stimulus lipopolysaccharide. Subcutaneously injected TNF/DC induce an unpolarized T(H)1/T(H)2 response and are not protective in the experimental autoimmune encephalomyelitis model. Although TNF/DC home to the draining lymph node, they remain negative for intracellular cytokine stainings. However, the nonmigrating, endogenous DC started to produce interleukin (IL)-12p40, TNF and little IL-6, IL-10, and MCP-1 in a bystander fashion. Together, DC matured with the inflammatory stimulus TNF remains responsive to further signals in vitro and in vivo. These signals can be provided by pathogens or the subcutaneous injection route, which can convert them from tolerogenic to immunogenic DC. These findings are important for selecting the appropriate injection route of human DC for tumor immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation* / drug effects
  • Cytokines / biosynthesis
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control
  • Female
  • Humans
  • Immune Tolerance
  • Injections, Subcutaneous
  • Interleukin-12
  • Interleukin-12 Subunit p35
  • Lipopolysaccharides / pharmacology
  • Lymph Nodes / cytology
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotides / pharmacology
  • Protein Subunits
  • Th1 Cells / immunology
  • Th2 Cells / immunology
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Cytokines
  • IL12A protein, human
  • Interleukin-12 Subunit p35
  • Lipopolysaccharides
  • Oligonucleotides
  • Protein Subunits
  • Tumor Necrosis Factor-alpha
  • Interleukin-12