Gene transfer of interleukin-1 receptor antagonist into the renal glomerulus via a mesangial cell vector.
Towards gene transfer-based therapies of renal glomerulonephritis, this study examines the feasibility of using a mesangial cell vector (J. Clin. Invest. 94, 497-505, 1994) engineered to secrete interleukin-1 receptor antagonist (IL-1ra). IL-1ra cDNA was introduced into cultured rat mesangial cells, and stably transfected vector cells were established. Compared to mock transfectants, the vector cells showed blunted expression of gelatinase B, stromelysin and monocyte chemoattractant protein-1 in response to IL-1 beta. The attenuated responses were transferable to untransfected cells by cross-feeding with vector cell-conditioned media. The vector cells were then delivered into the glomeruli of rats via the renal circulation. Compared to either unmodified or mock cell-containing glomeruli, the glomeruli transferred with vector cells showed repressed expression of gelatinase B in response to IL-1 beta. Transfer of vector cells thus conferred insensitivity to IL-1 on the glomerulus. This result indicates the feasibility of modifying glomerular microenvironment against certain pathogenic mediators via the ex vivo transfer of therapeutically-relevant genes to the glomerulus.
Yokoo
T
T
Department of Medicine, University College London Medical School, Rayne Institute, United Kingdom.
Kitamura
M
M
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D017364:Collagenases / Q000096:biosynthesis; D017077:Culture Media, Conditioned; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D005920:Glomerular Mesangium / Q000378:metabolism*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000302:isolation & purification; D014162:Transfection
D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D017364:Collagenases; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9