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 stu dy we have transfected rat macrophages with recombinant adenovirus expressi ng IL-4 (Ad-IL4) and demonstrated that these transfected macrophages develo p fixed properties as a result of transfection, as shown by reduced NO prod uction in response to IFN-gamma and TNF. Ad-IL4-transfected macrophages loc alized with enhanced efficiency to inflamed glomeruli after renal artery in jection in rats with NTN compared with adenovirus expressing beta -galactos idase (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-e xpressing macrophages produced a marked reduction in the severity of albumi nuria (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 glome ruli. Interestingly, the injection of IL-4-expressing macrophages into sing le kidney produced a marked reduction in the numbers of EDI-positive macrop hages 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 alt er the systemic development of the inflammatory response. Macrophage transf ection and delivery provide a valuable system to study and modulate inflamm atory disease and highlight the feasibility of macrophage-based gene therap y.