A new therapeutic strategy for rheumatoid arthritis (RA) aims to reinstate immune tolerance by administration of immunosuppressive autologous dendritic cells (DCs). In anticipation of a phase I clinical trial of tolerogenic DCs for the treatment of RA, a research group at Newcastle University, UK, investigated the therapeutic and immunomodulatory actions of these cells in a mouse model of the disease. In mice with established collagen-induced arthritis, treatment with tolerogenic DCs led to a reduction in disease severity and progression and, notably, a reduction in number of type 17 helper T (TH17) cells.

“TH17 cells are thought to be involved in the pathogenesis of RA,” says Catharien Hilkens, one of the study's investigators, “but nothing was known thus far about how tolerogenic DC treatment would affect this T-cell subset.” To investigate, the researchers generated murine tolerogenic DCs with reduced T-cell stimulatory capacity: bone-marrow derived DCs were treated with dexamethasone and vitamin D3 during maturation induced by the Toll-like receptor 4 ligand lipopolysaccharide.

The tolerogenic DCs, which exhibited a phenotype of semi-mature DCs, were injected intravenously into mice with collagen-induced arthritis at 3, 7 and 11 days after disease onset. After 4 weeks, clinical severity (based on redness and swelling of the paws) was inhibited in treated mice in comparison with untreated mice. Of note, this therapeutic effect was seen only with tolerogenic DCs pulsed with an autoantigen, bovine type II collagen, and was not seen with mature DCs.

The study also served to answer a number of practical questions relating to the clinical application of tolerogenic DCs that could not be readily addressed by in vitro experiments. For instance, an increase in dose from 1 × 106 cells to 2.5 × 106 cells per vaccination yielded no additional benefit, whereas the therapeutic effect was abrogated by use of a smaller dose, administration of a single injection as opposed to three, or use of an intraperitoneal route of administration.

The researchers also looked at how tolerogenic DC treatment modulated the T-cell response in vivo. In T cells isolated from treated mice, the proportions of IL-10-producing T cells were increased and pathogenic TH17 cells were decreased, although numbers of IL-17-producing γδT cells and TH1 cells were not affected.

“The mouse model of RA has been instrumental in learning more about how tolerogenic DC treatment works in established disease,” says Hilkens. The investigators plan to use the model to further optimize this therapy for RA, including testing the combination of tolerogenic DC treatment with other anti-inflammatory therapies. “The ultimate aim, of course,” says Hilkens, “is to test this new cellular therapy in patients with RA.”

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