title: Anti-T cell receptor monoclonal antibody prolongs transgene expression following adenovirus-mediated in vivo 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.
authors.affiliation: Children's Hospital Medical Center Division of Rheumatology, Cincinnati, OH 45229, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Sawchuk
authors.forename: G P
authors.initials: GP
authors.lastname: Boivin
authors.forename: L E
authors.initials: LE
authors.lastname: Duwel
authors.forename: W
authors.initials: W
authors.lastname: Ball
authors.forename: K
authors.initials: K
authors.lastname: Bove
authors.forename: B
authors.initials: B
authors.lastname: Trapnell
authors.forename: R
authors.initials: R
authors.lastname: Hirsch
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D007719:Knee Joint / Q000276:immunology / Q000473:pathology; D007763:Lac Operon; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D019076:Transgenes
chemical_list: D000911:Antibodies, Monoclonal; D011948:Receptors, Antigen, T-Cell