Systemic viral interleukin-10 gene delivery prevents cartilage invasion by human rheumatoid synovial tissue engrafted in SCID mice.
OBJECTIVE
To assess the effects of viral interleukin-10 (vIL-10) gene delivery on human rheumatoid synovial tissue.


METHODS
SCID mice were engrafted subcutaneously with human rheumatoid synovial tissue and homologous cartilage before systemic injection of 10(9) plaque-forming units of type 5 E1a Elb-deficient non-replicative adenovirus vector 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 later, the graft was removed for histologic analysis of cartilage invasion by synovial tissue. The number of CD3-positive mononuclear cells was assessed in the synovial tissue by immunohistology. Messenger RNA (mRNA) expression of matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), and proinflammatory cytokines was determined by polymerase chain reaction.


RESULTS
Systemic vIL-10 gene transfer resulted in high sustained production of vIL-10 protein in SCID mouse sera (mean +/- SD 25 +/- 5 ng/ml on day 40 post vector injection). Moreover, vIL-10 mRNA expression was detected in the synovial tissue 3 weeks after intravenous injection of AdvIL-10, reflecting the gene transfer in the human graft. In animals treated with AdvIL-10, cartilage invasion by rheumatoid synovial tissue was significantly inhibited 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 the synovium and perichondral resorption in the animals treated with AdvIL-10 gene were not significantly modified relative to the control vector. In animals treated with AdvIL-10, the MMP-3-TIMP-1 balance was partially restored, independent of the effect on mRNA expression of tumor necrosis factor a, IL-1, IL-6, or IL-8.


CONCLUSIONS
Systemic vIL-10 gene transfer prevented cartilage invasion by synovial tissue engrafted in SCID mice. This model offers the opportunity to study the biologic effects of gene transfer in vivo in rheumatoid synovium.
Jorgensen
C
C
Service d'Immuno-Rhumatologie, Hôpital Lapeyronie, and INSERM, Montpellier, France.
Apparailly
F
F
Canovas
F
F
Verwaerde
C
C
Auriault
C
C
Jacquet
C
C
Sany
J
J
D000256:Adenoviridae; D000818:Animals; D002356:Cartilage / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D018014:Gene Transfer Techniques; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D013583:Synovial Membrane / Q000201:enzymology / Q000276:immunology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D007375:Interleukin-1; D016209:Interleukin-8; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019278:Matrix Metalloproteinase 3