Macrophages transfected with adenovirus to express IL-4 reduce inflammation in experimental glomerulonephritis.
Nephrotoxic nephritis (NTN) is characterized by acute macrophage-dependent inflammation and serves as a model of human glomerulonephritis. In this study we have transfected rat macrophages with recombinant adenovirus expressing IL-4 (Ad-IL4) and demonstrated that these transfected macrophages develop fixed properties as a result of transfection, as shown by reduced NO production in response to IFN-gamma and TNF. Ad-IL4-transfected macrophages localized with enhanced efficiency to inflamed glomeruli after renal artery injection in rats with NTN compared with adenovirus expressing beta-galactosidase (Ad-beta gal)-transfected macrophages and produced elevated levels of the cytokine in glomeruli in vivo for up to 4 days. The delivery of IL-4-expressing macrophages produced a marked reduction in the severity of albuminuria (day 2 albuminuria, 61 +/- 15 mg/24 h) compared with unmodified NTN (day 2 albuminuria, 286 +/- 40 mg/24 h; p < 0.01), and this was matched by a reduction in the number of ED1-positive macrophages infiltrating the glomeruli. Interestingly, the injection of IL-4-expressing macrophages into single kidney produced a marked reduction in the numbers of ED1-positive macrophages in the contralateral noninjected kidney, an effect that could not be mimicked by systemic delivery of IL-4-expressing macrophages. This implies that the presence of IL-4-expressing macrophages in a single kidney can alter the systemic development of the inflammatory response. Macrophage transfection and delivery provide a valuable system to study and modulate inflammatory disease and highlight the feasibility of macrophage-based gene therapy.
Kluth
D C
DC
Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom. d.c.kluth@abdn.ac.uk
Ainslie
C V
CV
Pearce
W P
WP
Finlay
S
S
Clarke
D
D
Anegon
I
I
Rees
A J
AJ
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016026:Bone Marrow Transplantation; D002452:Cell Count; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control* / Q000821:virology; D007269:Injections, Intra-Arterial; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation / Q000821:virology*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D011507:Proteinuria / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma