Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects.
Adenoviral vectors were used to deliver genes encoding a soluble interleukin 1 (IL-1)-type I receptor-IgG fusion protein and/or a soluble type I tumor necrosis factor alpha (TNFalpha) receptor-IgG fusion protein directly to the knees of rabbits with antigen-induced arthritis. When tested individually, knees receiving the soluble IL-1 receptor had significantly reduced cartilage matrix degradation and white blood cell infiltration into the joint space. Delivery of the soluble TNFalpha receptor was less effective, having only a moderate effect on white blood cell infiltration and no effect on cartilage breakdown. When both soluble receptors were used together, there was a greater inhibition of white blood cell infiltration and cartilage breakdown with a considerable reduction of synovitis. Interestingly, anti-arthritic effects were also seen in contralateral control knees receiving only a marker gene, suggesting that sustained local inhibition of disease activity in one joint may confer an anti-arthritic effect on other joints. These results suggest that local intra-articular gene transfer could be used to treat systemic polyarticular arthritides.
Ghivizzani
S C
SC
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh PA 1526, USA.
Lechman
E R
ER
Kang
R
R
Tio
C
C
Kolls
J
J
Evans
C H
CH
Robbins
P D
PD
D000256:Adenoviridae; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000628:therapy*; D002358:Cartilage, Articular / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005819:Genetic Markers; D015316:Genetic Therapy; D005822:Genetic Vectors; D007074:Immunoglobulin G; D007596:Joints / Q000473:pathology; D007962:Leukocytes / Q000502:physiology; D008156:Luciferases / Q000096:biosynthesis; D051379:Mice; D009928:Organ Specificity; D011817:Rabbits; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013583:Synovial Membrane / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D005819:Genetic Markers; D007074:Immunoglobulin G; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases