Gram-negative enterobacteria induce tolerogenic maturation in dexamethasone conditioned dendritic cells

PLoS One. 2012;7(12):e52456. doi: 10.1371/journal.pone.0052456. Epub 2012 Dec 27.

Abstract

Dendritic cells have been investigated in clinical trials, predominantly with the aim of stimulating immune responses against tumours or infectious diseases. Thus far, however, no clinical studies have taken advantage of their specific immunosuppressive potential. Tolerogenic DCs may represent a new therapeutic strategy for human immune-based diseases, such as Crohn's disease, where the perturbations of the finely tuned balance between the immune system and the microflora result in disease. In the present report, we describe the generation of tolerogenic DCs from healthy donors and Crohn's disease patients using clinical-grade reagents in combination with dexamethasone as immunosuppressive agent and characterize their response to maturation stimuli. Interestingly, we found out that dexamethasone-conditioned DCs keep their tolerogenic properties to Gram-negative bacteria. Other findings included in this study demonstrate that the combination of dexamethasone with a specific cytokine cocktail yielded clinical-grade DCs with the following characteristics: a semi-mature phenotype, a pronounced shift towards anti-inflammatory versus inflammatory cytokine production and low T-cell stimulatory properties. Importantly, in regard to their clinical application, the tolerogenic phenotype of DCs remained stable after the elimination of dexamethasone and after a second stimulation with LPS or bacteria. All these properties make this cell product suitable to be tested in clinical trials of inflammatory conditions including Crohn's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Bacterial / immunology
  • Case-Control Studies
  • Crohn Disease / immunology
  • Cytokines / biosynthesis
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / microbiology*
  • Dexamethasone / pharmacology*
  • Enterobacteriaceae / immunology
  • Enterobacteriaceae / physiology*
  • Humans
  • Immune Tolerance / drug effects*
  • Monocytes / cytology
  • Phenotype
  • T-Lymphocytes / immunology
  • T-Lymphocytes / microbiology

Substances

  • Antigens, Bacterial
  • Cytokines
  • Dexamethasone

Grants and funding

This work was supported by grant SAF 2009-07272 from the Ministerio de Ciencia e Innovacion, grant TRA-097 from the Ministerio de Sanidad y Politica Social, and by Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). DB-R is supported by CIBERehd and by the Instituto de Salud Carlos III, RC is funded by a FI fellowship from the Generalitat de Catalunya. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.