Intra-articular IL-10 gene transfer regulates the expression of collagen-induced arthritis (CIA) in the knee and ipsilateral paw

Abstract

SUMMARYWe studied the effects of local IL-10 application, introduced by a recombinant human type 5 adenovirus vector, in the mouse knee joint during the early phase of CIA. One intra-articular injection with the IL-10-expressing virus (Ad5E1mIL-10) caused substantial over-expression of IL-10 in the mouse knee joint, using virus dosages which did not induce distracting inflammation. High expression of IL-10 was noted for a few days, being maximal at day 1. One intra-articular injection of Ad5E1mIL-10 in the knee joints of collagen type II (CII)-immunized mice, before onset of CIA was noted, reduced the incidence of collagen arthritis in that knee. Of high interest, the protective effect of local IL-10 expression by Ad5E1mIL-10 was not restricted to the knee joint alone. The arthritis incidence in the ipsilateral paw was highly suppressed. In contrast, local IL-10 over-expression was not effective when treatment was started after onset of CIA. Further analysis in the acute streptococcal cell wall-induced arthritis model revealed that local IL-10 over-expression markedly suppressed the production of tumour necrosis factoralpha (TNF-a ) and IL-1a , but had no significant effect on IL-1b and IL-12 production in the inflamed synovium. These data indicate that local over-expression of IL-10 in the knee joint of mice regulates the expression of collagen arthritis, probably through down-regulation of TNF-a .

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

“…Intraarticular administration of IL-10 did not reduce the severity of arthritis (34), whereas systemic injection with recombinant IL-10 effectively inhibited disease (36). We detected a higher proportion of IL-10-producing T cells in the spleen after tolerogenic DC treatment, suggesting a systemic increase in IL-10.…”

“…Although it has been shown that treatment with recombinant IL-10 or IL-10-producing T cells is effective for preventing arthritis in mouse models (34,35), contradictory observations have been made regarding the therapeutic effect of IL-10 in established arthritis. Intraarticular administration of IL-10 did not reduce the severity of arthritis (34), whereas systemic injection with recombinant IL-10 effectively inhibited disease (36).…”

Induction of cartilage damage by overexpression of T cell interleukin‐17A in experimental arthritis in mice deficient in interleukin‐1

“…As a control, AdDel70-3 was injected into the left knee joint. We have previously shown that this dose of adenoviral vector does not induce any inflammatory response after IA injection into the mouse knee joint (24). Several days thereafter, mice were killed by cervical dislocation, and the knee joints were harvested for further processing.…”

The contralateral effect conferred by intra-articular adenovirus-mediated gene transfer of viral IL-10 is specific to the immunizing antigen

“…Indeed, several groups observe high systemic levels of transgene products after local delivery of genes to joints. 8,11,12 However, in our experiments, systemic transgene levels were either below detectable levels or too low to confer a therapeutic effect in our model systems.…”