Abstract
BackgroundRheumatoid Arthritis (RA) is a chronic immune mediated disease associated with deregulation of many cell types. It has been reported that different T cell subsets have opposite effects in disease pathogenesis, in particular Th17 and Treg cells.Methodology and FindingsWe investigated whether non-depleting anti-CD4 monoclonal antibodies, which have been reported as pro-tolerogenic, can lead to protection from chronic autoimmune arthritis in SKG mice – a recently described animal model of RA – by influencing the Th17/Treg balance. We found that non-depleting anti-CD4 prevented the onset of chronic autoimmune arthritis in SKG mice. Moreover, treated mice were protected from the induction of arthritis up to 60 days following anti-CD4 treatment, while remaining able to mount CD4-dependent immune responses to unrelated antigens. The antibody treatment also prevented disease progression in arthritic mice, although without leading to remission. Protection from arthritis was associated with an increased ratio of Foxp3, and decreased IL-17 producing T cells in the synovia. In vitro assays under Th17-polarizing conditions showed CD4-blockade prevents Th17 polarization, while favoring Foxp3 induction.ConclusionsNon-depleting anti-CD4 can therefore induce long-term protection from chronic autoimmune arthritis in SKG mice through reciprocal changes in the frequency of Treg and Th17 cells in peripheral tissues, thus shifting the balance towards immune tolerance.
Highlights
Rheumatoid arthritis (RA) is a common chronic autoimmune inflammatory disease characterized by destruction of the synovial joints, leading to progressive disability, increased co-morbidity and premature mortality [1,2]
SKG mice develop chronic autoimmune arthritis upon systemic curdlan immunization initial reports have suggested that SKG mice develop chronic autoimmune arthritis spontaneously [18], it was later confirmed that disease induction requires exposure to yeast wall extract or purified b-glucans, like curdlan or laminarin, acting through the pattern recognition receptor Dectin-1 [23]
Both male and female mice developed arthritis, the disease was more severe in females (Figure 1B)
Summary
Rheumatoid arthritis (RA) is a common chronic autoimmune inflammatory disease characterized by destruction of the synovial joints, leading to progressive disability, increased co-morbidity and premature mortality [1,2]. Both genetic and environmental factors are known to contribute to the development of the disease [3]. Monoclonal antibodies (MAbs) targeting key T cell molecules (such as co-receptor and co-stimulation) have been suggested as drugs capable of achieving long-term protection from the disease, with the potential of leading to immune tolerance, following a short treatment [14]. It has been reported that different T cell subsets have opposite effects in disease pathogenesis, in particular Th17 and Treg cells
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