Systemic viral interleukin-10 gene delivery prevents cartilage invasion byhuman rheumatoid synovial tissue engrafted in SCID mice

Objective. To assess the effects of viral interleukin-10 (vIL-10) gene deli very on human rheumatoid synovial tissue. Methods. SCID mice were engrafted subcutaneously with human rheumatoid syno vial tissue and homologous cartilage before systemic injection of 109 plaqu e-forming units of type 5 E1a E1b-deficient nonreplicative adenovirus vecto r containing the vIL-10 gene under control of the cytomegalovirus promoter (AdvIL-10; n = 10) or a control gene (AdvIL-10mut; n = 7). Three weeks late r, the graft was removed for histologic analysis of cartilage invasion by s ynovial tissue. The number of CD3-positive mononuclear cells was assessed i n the synovial tissue by immunohistology. Messenger RNA (mRNA) expression o f matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinase s 1 (TIMP-1), and proinflammatory cytokines was determined by polymerase ch ain reaction. Results. Systemic vIL-10 gene transfer resulted in high sustained productio n of vIL-10 protein in SCID mouse sera (mean +/- SD 25 +/- 5 ng/ml on day 4 0 post vector injection). Moreover, vIL-10 mRNA expression was detected in the synovial tissue 3 weeks after intravenous injection of AdvIL-10, reflec ting the gene transfer in the human graft. In animals treated with AdvIL-10 , cartilage invasion by rheumatoid synovial tissue was significantly inhibi ted compared with the control vector (mean +/- SD histologic score 2.5 +/- 0.52 versus 0.75 +/- 0.8; P < 0.0001). The number of T cells infiltrating t he synovium and perichondral resorption in the animals treated with AdvIL-1 0 gene were not significantly modified relative to the control vector. In a nimals treated with AdvIL-10, the MMP3-TIMP-1 balance was partially restore d, independent of the effect on mRNA expression of tumor necrosis factor al pha, IL-1, IL-6, or IL-8. Conclusion. Systemic vIL-10 gene transfer prevented cartilage invasion by s ynovial tissue engrafted in SCID mice. This model offers the opportunity to study the biologic effects of gene transfer in vivo in rheumatoid synovium .