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Modulation of established murine collagen-induced arthritis by a single inoculation of short-term lipopolysaccharide-stimulated dendritic cells
  1. L Salazar1,
  2. O Aravena1,
  3. P Abello1,
  4. A Escobar1,
  5. J Contreras-Levicoy1,
  6. N Rojas-Colonelli1,
  7. D Catalán1,
  8. A Aguirre1,
  9. R Zúñiga1,
  10. B Pesce1,
  11. C González2,
  12. R Cepeda2,
  13. M Cuchacovich3,
  14. M C Molina1,
  15. F Salazar-Onfray1,
  16. M Delgado4,
  17. R E Toes5,
  18. J C Aguillón1
  1. 1
    Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile
  2. 2
    Departamento de Patología Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile
  3. 3
    Sección de Reumatología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Santiago, Chile
  4. 4
    Instituto de Parasitologia y Biomedicina, CSIC, Granada, Spain
  5. 5
    Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
  1. J C Aguillón, Programa Disciplinario de Inmunología, ICBM, Facultad de Medicina, Universidad de Chile. Av. Independencia 1027, Santiago, Chile; jaguillo{at}med.uchile.cl

Abstract

Background: The use of regulatory or immature dendritic cells (DCs) as tools for modulating experimental rheumatoid arthritis is very recent. Tumour necrosis factor (TNF)-stimulated DCs have been shown to restore tolerance in experimental autoimmune encephalomyelitis and collagen-induced arthritis (CIA).

Objective: We investigated the capacity of short-term lipopolysaccharide (LPS)-stimulated DCs pulsed with type II collagen (CII) to induce tolerance against established CIA.

Methods: Bone marrow-derived DCs were generated in the presence of granulocyte monocyte colony-stimulating factor (GM-CSF). After CIA induction, mice were injected at day 35 with a single dose of 4- or 24-h LPS-stimulated DCs that had been loaded with CII (4hLPS/CII/DCs or 24hLPS/CII/DCs). Arthritis progression was monitored by clinical and histological evaluations.

Results: Flow cytometry of 4hLPS/CII/DCs showed intermediate CD40 and CD86 expression, lower than that of 24hLPS/CII/DCs (fully mature) and higher than that of CII/DCs (immature). A functional assay showed that 4hLPS/CII/DCs display increased endocytosis ability with respect to 24hLPS/CII/DCs, indicating a semimature state. The single inoculation of 4hLPS/CII/DCs in mice with established CIA reduced disease severity significantly over time. Histological evaluation of mice treated with 4hLPS/CII/DCs revealed diminished inflammatory synovitis, cartilage damage and fibrosis. Co-cultures of DCs with splenocytes from CIA mice showed that collagen-specific interferon (IFN)γ production was dramatically inhibited by 4hLPS/CII/DCs. 4hLPS/CII/DCs were high IL10 producers, which could explain the inhibition of arthritis progression in mice receiving this treatment because neither antibodies nor regulatory CD4+CD25+Foxp3+ T lymphocytes were demonstrated to be involved.

Conclusion: Short-term LPS-modulated DCs inoculation interferes with CIA progression when loaded with CII.

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Footnotes

  • Funding: This study was supported by Fondecyt-Chile (104-0860 and 107-0553).

  • Competing interests: None declared.

  • Ethics approval: All protocols were approved by the University of Chile Bioethics Committee.

  • LS, OA, AE, JC-L, N R-C, DC, AA, RZ, F S-O and JCA are members of the Millennium Nucleus on Immunology and Immunotherapy – Chile (P04/030-F).

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