Effective Treatment of Established Murine Collagen-Induced Arthritis by Systemic Administration of Dendritic Cells Genetically Modified to Express IL-4

Abstract

Dendritic cells (DC) are APCs that are able to stimulate or inhibit immune responses, depending on levels of expression of MHC class I and II costimulatory molecules and cytokines. Our previous studies have suggested that the observed contralateral effect, where injection of a vector carrying certain immunomodulatory genes into one joint resulted in inhibition of arthritis in untreated joints, is mediated by in vivo modification of DC. Therefore, we have examined the ability of genetically modified DC to suppress established murine collagen-induced arthritis (CIA) after i.v. delivery. IL-4 has been shown to partially reduce the severity of CIA after repeated injection of recombinant protein or by injection of an adenoviral vector expressing IL-4. Here we demonstrate that i.v. injection of immature DC, infected with an adenoviral vector expressing IL-4, into mice with established CIA resulted in almost complete suppression of disease, with no recurrence for up to 4 wk posttreatment. Injection i.v. of fluorescently labeled DC demonstrated that the cells rapidly migrated to the liver and spleen after 6 h and to the lymph nodes by 24 h. In culture, spleen cells from DC/IL-4-treated mice produced less IFN-γ after stimulation by collagen than did control groups. In addition, DC/IL-4 administration decreased the level of specific Abs against type II collagen, in particular the IgG2 Th1 isotype 14 days posttreatment. These results demonstrate the ability to treat effectively established murine arthritis by systemic administration of DC expressing IL-4.

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

“…Previous studies focused on the ability of tolerogenic DCs to inhibit Th1 cell responses (15,(17)(18)(19)30). In contrast, we observed an improvement in arthritis without an effect on Th1 cell responses.…”

“…DCs with potent and stable tolerogenic activity can be generated in vitro by genetic or pharmacologic modification (14). For instance, DCs transduced with FasL or IL-4 have been used to prevent CIA and to inhibit arthritis symptoms in mice with established disease (15)(16)(17). Tolerogenic DCs modified by drugs (dexamethasone; Bay 11-7082) or cytokines (tumor necrosis factor [TNF]) have been used successfully to prevent the onset of CIA (18)(19)(20)(21)(22) or to suppress established arthritis in a different model, the antigeninduced arthritis model (23).…”

Electro-gene therapy of collagen-induced arthritis by using an expression plasmid for the soluble p75 tumor necrosis factor receptor-Fc fusion protein

“…44 The thickness of each paw was also measured using a spring-load caliper. Scoring of arthritic index and measuring of paw thickness were done by two independent observers who were blinded with regard to the experimental groups.…”

An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint

“…The 'contralateral effect', that is the administration of the expression vector in one joint to suppress arthritis in distal or contralateral joints, has been reported by many laboratories. [47][48][49][50][51][52] This study, which shows activation of the IL-1/IL-6 enhancer-promoter in the contralateral joints by signals derived from the arthritic joint, suggests that there is crosstalk between joints. Treatment of one joint may interfere with this crosstalk and by this suppresses arthritis in the other contralateral joint.…”