During the development of gene therapies for arthritis, it was noted that the adenoviral, in vivo delivery of the viral interleukin-10 (vII-10) gene to the joints of mice with collagen-induced (c.i.a.) and rabbits with antigen-induced arthritis had an unexpected and highly important effect: it suppressed disease activity not only in the injected paw, but also in non-injected paws of the same animal. The present proposal aims to understand the mechanism underlying this effect. Under investigation is the hypothesis that introduction of adenoviral vectors carrying vIL-10 into the intra-and peri-articular regions of the arthritic paws results in the transduction of a leukocyte, probably a dendritic cell, with the ability to suppress disease. These cells are further postulated to traffic to other joints as well as lymphoid organs, as a result of which they suppress arthritis in multiple joints. In support of this hypothesis, it has been shown that adenoviral transfer of marker genes into one diseased joint results in the appearance of transduced cells resembling dendritic cells in the uninjected, contralateral joint of the same animal. Moreover, vII1-10 transduced adherent splenocytes recovered from sensitized mice could suppress disease when transferred to recipient animal either i .p. or i.a. In the latter case a contralateral effect was noted. To evaluate the above hypothesis, the identity of the anti-arthritic cells will be confirmed, their ability to traffic will be assessed and the effect of vII-10 on their ability to activate T-lymphocytes will be measured.
| Bertone, A L; Pittman, D D; Bouxsein, M L et al. (2004) Adenoviral-mediated transfer of human BMP-6 gene accelerates healing in a rabbit ulnar osteotomy model. J Orthop Res 22:1261-70 |
