Abstract
Dendritic cells (DC) have the potential to control the outcome of autoimmunity by modulating the immune response. In this study, we tested the ability of Fasciola hepatica total extract (TE) to induce tolerogenic properties in CpG-ODN (CpG) maturated DC, to then evaluate the therapeutic potential of these cells to diminish the inflammatory response in collagen induced arthritis (CIA). DBA/1J mice were injected with TE plus CpG treated DC (T/C-DC) pulsed with bovine collagen II (CII) between two immunizations with CII and clinical scores CIA were determined. The levels of CII-specific IgG2 and IgG1 in sera, the histological analyses in the joints, the cytokine profile in the draining lymph node (DLN) cells and in the joints, and the number, and functionality of CD4+CD25+Foxp3+ T cells (Treg) were evaluated. Vaccination of mice with CII pulsed T/C-DC diminished the severity and incidence of CIA symptoms and the production of the inflammatory cytokine, while induced the production of anti-inflammatory cytokines. The therapeutic effect was mediated by Treg cells, since the adoptive transfer of CD4+CD25+ T cells, inhibited the inflammatory symptoms in CIA. The in vitro blockage of TGF-β in cultures of DLN cells plus CII pulsed T/C-DC inhibited the expansion of Treg cells. Vaccination with CII pulsed T/C-DC seems to be a very efficient approach to diminish exacerbated immune response in CIA, by inducing the development of Treg cells, and it is therefore an interesting candidate for a cell-based therapy for rheumatoid arthritis (RA).
Highlights
rheumatoid arthritis (RA) is an autoimmune disease that affects 1–2% of the population world wide and is caused by the loss of immunological self-tolerance leading to infiltration of the joint synovium by activated inflammatory cells, synovial hyperplasia, neoangiogenesis and the progressive destruction of cartilage and bone [1]
To optimize the generation of tolerogenic Dendritic cells (DC), we explored whether the activation of DC with total extract (TE) together with different TLR ligands could improve the tolerogenic properties of these cells
We demonstrated that TE modulated LPS-induced DC maturation, increases the amount of IL-10 and reduces IL-12p70
Summary
RA is an autoimmune disease that affects 1–2% of the population world wide and is caused by the loss of immunological self-tolerance leading to infiltration of the joint synovium by activated inflammatory cells, synovial hyperplasia, neoangiogenesis and the progressive destruction of cartilage and bone [1]. DC are the most potent antigen presenting cells, which can be manipulated to activate lymphocytes, and to induce T cell-tolerance to specific antigens, thereby minimizing autoimmune reactions [4]. Both immature and semi-mature DC have been associated with an induction of tolerance through the generation of regulatory T cells, the induction of apoptosis or the anergy of autoreactive effector cells [5]. Manipulation of immature DC through different strategies have shown to be an effective methodology to inhibit the exacerbated immune responses in autoimmune diseases [6]. Infection with Fasciola hepatica induces the suppression of immune responses to autoantigens and attenuates the clinical signs of experimental autoimmune encephalomyelitis [11]
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