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

Abstract

We have demonstrated previously that local, adenoviralmediated gene transfer of vIL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. These therapeutic effects observed in distant untreated joints following local intra-articular gene delivery have been termed the 'contralateral effect'. To begin to understand the underlying immunologic mechanism that confers this effect, a dualantigen model of antigen-induced arthritis (AIA) in rabbit knee joints was utilized. Rabbits were immunized against two antigens, ovalbumin and keyhole limpet hemocyanin, and AIA generated by intra-articular injection of each antigen into contralateral knees. Intra-articular adenovirus-mediated gene transfer of vIL-10 significantly reduced intra-articular leukocytosis and cartilage matrix degradation, while preserving near normal levels of cartilage matrix synthesis within treated joints. However, no antiarthritic effect was conferred in the contralateral control joints that received only a marker gene, in contrast to the results seen in a single-antigen AIA model. These results suggest that the distant antiarthritic effects associated with local gene delivery to joints are antigen-specific, and not due to vIL-10-induced generalized immunosuppression of the animal.

Gene therapy for arthritis

“…For example, intra-articular injection of an adenoviral vector expressing vIL-10, the Epstein-Barr virus encoded IL-10 gene, resulted in a reduction in disease pathology, reducing the white blood cell infiltrate and improving cartilage metabolism in the injected knee, but also in the contralateral control knee. 90 This effect was termed the contralateral effect because of the initial observation made in a rabbit knee model of arthritis. Although this contralateral effect was initially observed with intraarticular or periarticular injection of adenoviral vectors a similar effect has been observed with retroviral vectors, liposomes, and even with injection of genetically modified synovial fibroblasts into rabbit knees.…”

Cartilage-Specific Matrix and Integrin Expression in Three-Dimensional Articular Chondrocyte Cultures Overexpressing Human Interleukin-10

“…Over the last decade the anti-infl ammatory potential of IL-10 in arthritis has been proposed through in vivo animal studies indicating that this immunoregulatory cytokine (IL-10) might be a promising candidate for gene therapy in the infl amed joint (Lechman et al 1999(Lechman et al , 2003Neumann et al 2002;Van de Loo and van den Berg, 2002;Gelse et al 2003;Zhang et al 2004;Kuroda et al 2006). Only differentiated chondrocytes can be used for chondrocyte implantation to produce a stable cartilage-specifi c matrix and it remains unclear whether high concentrations of IL-10 might affect the differentiated phenotype of chondrocytes.…”

“…Therefore, high virus doses are necessary for in vivo transduction strategies. This approach requires the dissiminated transduction of adjacent tissues in the joint; systemic distribution of the vectors in the patient and systemic adverse effects of the vector such as immunosuppression (Van de Loo and Van den Berg, 2002;Lechman et al 2003). For these reasons, ex vivo transfection strategies are necessary to achieve suffi cient IL-10 or anabolic growth factors overexpressing chondrocytes which might be implanted in cartilage defects as a strong localized transgene source to inhibit post-traumatic joint infl ammation and to support cartilage repair (Gelse et al 2003;Gelse and Schneider, 2006).…”

Gene Therapy Challenges in Arthritis

“…The contralateral effect doesn't depend on : 1. the strategy using ex vivo or in vivo (Kim et al, 2002;Kim et al, 2005;Whalen et al, 1999) 2. the vector injected in vivo because it was observed using viral vector, adenovirus, adeno-associated virus and non viral vector (Chan et al, 2002;Ghivizzani et al, 1998;, 3. the model of arthritis because it is observed in CIA, AIA and Streptococcal Cell wall (SCW)-induced arthritis (Chan et al, 2002;Kim et al, 2005;Lechman et al, 2003), 4. species as observed in rabbits , in rats , in mice and also in human clinical trials (Chan et al, 2002;Ghivizzani et al, 1998;Wehling et al, 2009). The reason of the contralateral effect with in vivo gene transfer is not well known.…”