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Modulation of established murine collagen-induced arthritis by a single inoculation of short-term lipopolysaccharide-stimulated dendritic cells
  1. Lorena Salazar (lsalazar{at}med.uchile.cl)
  1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
    1. Octavio Aravena (oaraven{at}yahoo.com)
    1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
      1. Paula Abello (abellopauly{at}hotmail.com)
      1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
        1. Alejandro Escobar (jano{at}med.uchile.cl)
        1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
          1. Juan Contreras-Levicoy (jc_ancud{at}yahoo.com)
          1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
            1. Nicole Rojas-Colonelli (nicole.pepi{at}gmail.com)
            1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
              1. Diego Catalán (diegocatalanm{at}hotmail.com)
              1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
                1. Adam Aguirre (adaguirr{at}udec.cl)
                1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
                  1. Roberto Zúñiga (rzuniga{at}med.uchile.cl)
                  1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
                    1. Barbara Pesce (bpesce{at}gmail.com)
                    1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
                      1. Carlos González (cmgonza{at}gmail.com)
                      1. Depto de Patología Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Chile
                        1. Raquel Cepeda (rcepeda{at}uchile.cl)
                        1. Depto de Patología Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Chile
                          1. Miguel Cuchacovich (mcuchaco{at}yahoo.com)
                          1. Sección de Reumatología, Departamento de Medicina, Hospital Clinico Universidad de Chile, Chile
                            1. Maria Carmen Molina (mcmolina{at}med.uchile.cl)
                            1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
                              1. Flavio Salazar-Onfray (fsalazar{at}med.uchile.cl)
                              1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile
                                1. Mario Delgado (mdelgado{at}ipb.csic.es)
                                1. Instituto de Parasitologia y Biomedicina, CSIC, Granada, Spain
                                  1. René E Toes (r.e.m.toes{at}lumc.nl)
                                  1. Department of Rheumatology, Leiden University Medical Centre, Netherlands
                                    1. Juan Carlos Aguillón (jcaguillo{at}gmail.com)
                                    1. Programa Disciplinario de Inmunologia, ICBM, Facultad de Medicina, Universidad de Chile, Chile

                                      Abstract

                                      The use of regulatory or immature dendritic cells (DCs) as tools for modulating experimental rheumatoid arthritis is very recent. 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 GM-CSF. After CIA induction, mice were injected at day 35 with a single dose of 4- or 24-hour LPS-stimulated DCs that had been loaded with CII (CII/DCs, 4hLPS/CII/DCs or 24hLPS/CII/DCs). Arthritis progression was monitored by clinical and histologic 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 semi-mature state. The single inoculation of 4hLPS/CII/DCs in mice with established CIA reduced significantly disease severity over time. Histologic 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 IFNγ production was dramatically inhibited by 4hLPS/CII/DCs. 4hLPS/CII/DCs were high IL-10 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.

                                      • CIA
                                      • LPS
                                      • arthritis
                                      • dendritic cells
                                      • regulatory cells

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