Anti-T Cell Receptor Monoclonal Antibody Prolongs Transgene Expression Following Adenovirus-Mediated <i>In Vivo</i> Gene Transfer to Mouse Synovium

Abstract

There are no cures for rheumatoid arthritis (RA) or other inflammatory autoimmune arthropathies. Gene transfer to the synovium would allow administration of anti-inflammatory gene products directly to the articular space where they could exert a local down-regulatory effect on the autoimmune process. Several well-characterized murine models of arthritis closely resemble RA immunologically, genetically, and histopathologically. To determine whether the mouse could serve as a model for gene transfer to the synovium, a methodology was developed to reproducibly inject a 5-microliter volume into the articular space of the mouse knee. Using this approach, Av1LacZ4, an E1a-E3-deleted adenoviral (Ad5) vector expressing the lacZ transgene, was delivered intra-articularly (5 x 10(8) pfu). lacZ expression was observed in the articular synovium for at least 14 days. Biochemical quantitation demonstrated a gradual loss of transgene expression, associated with an early, predominantly neutrophilic, inflammatory response that progressed to a lymphocytic infiltrate, followed by gradual resolution over a 3-week period. Pretreatment with the anti-TCR monoclonal antibody (mAb) H57 resulted in a significant reduction in lymphocytic infiltration and a prolongation of transgene expression. These data demonstrate that transgenes can be delivered to the mouse knee joint space, affording a powerful tool to test the potential of gene therapy as a therapeutic modality for RA. As in other systems, the immune response against recombinant adenoviral vectors may limit the extent and duration of gene expression in the synovium. Anti-T cell mAbs may be useful in inhibiting this immune response.