While screening several anti-inflammatory gene products for efficacy in rabbit and murine models of RA by intra-articular adenoviral injection, a therapeutic effect was observed in both the treated and untreated contralateral joints. This contralateral effect was observed following adenoviral gene transfer of IL-1Ra, sIL-1 receptor, sTNF-receptor, vIL-10 and IL-4. Several different experiments suggested that the therapeutic effect may be due, in part, to the migration of a population of virally transduced antigen presenting cells (APC) from the treated joint to the regional lymph nodes and the untreated arthritic joints. Consistent with this model, we have demonstrated that direct intravenous injection of genetically modified DC expressing IL-4, FasL, IL-1Ra or CTLA4-Ig resulted in suppression or elimination of established collagen induced arthritis. However, intra-articular ex vivo delivery of retrovirus transduced syngeneic synoviocytes expressing anti-inflammatory factors conferred a similar therapeutic effect in treated as well as untreated contralateral joints. The results from our ex vivo and in vivo studies suggested that trafficking of vector-modified inflammatory cells may not be the main mechanism responsible for the observed contralateral effect. We now propose that local, intra-articular expression of anti-inflammatory factors may be able to modify the function of APCs that are then able to modulate the immune response in the contralateral joint. In support of this model, injection of APC treated with either recombinant IL-10 protein or infected with Ad.vIL-10 were able to block the DTH response in both the treated and untreated paws. We also have demonstrated that exosomes derived from Ad.vIL-10 infected APC were able to reduce the DTH response in both the treated and untreated paws. Taken together these results suggest that modified APC as well as APC derived-exosomes can confer a novel protective, anti-inflammatory effect in treated and untreated contralateral joints.
Authors and Affiliations
School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
PD Robbins, ER Lechman, S-H Kim, A Gambotto, J Whalen, Z Mi & TJ Oligino
Center for Molecular Orthopaedics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA