Transfer of genetically engineered macrophages into the glomerulus

Kitamura, Masanori; Sütö, Tamás

doi:10.1038/ki.1997.174

Cited by 25 publications

(26 citation statements)

References 32 publications

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“…Recently the same approach has been used to express 15-lipoxygenase in glomeruli of rats with NTN, resulting in a reduction in albuminuria but no effect on macrophage infiltration (25). Cell-based systems have proven more successful to deliver genes to glomeruli using either mesangial cells (26) or macrophages (10,27,28), with macrophages of particular value in the modification of inflammatory disease (10,29) due to their ability to infiltrate a focus of injury. Injection of adenovirus-transfected macrophages provides a highly effective method for glomerular gene transfer, with nearly 100% of glomeruli containing transfected macrophages.…”

Section: Discussionmentioning

confidence: 99%

Macrophages Transfected with Adenovirus to Express IL-4 Reduce Inflammation in Experimental Glomerulonephritis

Kluth

Ainslie

Pearce

et al. 2001

The Journal of Immunology

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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-γ 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 β-galactosidase (Ad-βgal)-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.

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Section: Discussionmentioning

confidence: 99%

Macrophages Transfected with Adenovirus to Express IL-4 Reduce Inflammation in Experimental Glomerulonephritis

Kluth

Ainslie

Pearce

et al. 2001

The Journal of Immunology

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“…37 Heikkila et al 38 transfected glomeruli in pigs with recombinant adenovirus with high efficiency using chilled isolated perfusion of a single kidney, however, in general, adenoviruses do not transfect the glomeruli in rats even following cold perfusion or viral modification. [39][40][41][42] Kitamura has used retroviral transfected mesangial cells 43 and macrophages 44 to act as delivery vehicles to the glomerulus but in the case of the macrophages the length of expression has not been analysed nor the influence on the severity of a disease model. Recently, in mice bone marrow macrophages transfected to express human glucocerebrosidase also localised to glomeruli in LPS-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Gene transfer into inflamed glomeruli using macrophages transfected with adenovirus

et al. 2000

Gene Ther

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In vivo gene transfer to sites of inflammatory disease provides a novel method both for studying the effects of cytokines and growth factors, and for therapeutic intervention. Macrophages play a pivotal role in the development and control of inflammation and are therefore logical cells to use for genetic modification and in vivo gene delivery. In this study we show that macrophages (both cell lines and primary cultures) can be transfected by recombinant adenoviruses expressing ␤-galactosidase, that the macrophages become activated by the transfection process as determined by generation of nitric oxide and can be easily manipulated

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“…The induction of mesangial cell tolerance by activated macrophages may be caused by direct cell-to-cell contact (35) or crosstalk via macrophage-derived paracrine factors (36,37). Alternatively, once activated, mesangial cells may produce macrophagedeactivating factors that suppress the effector function of macrophages (21,38,39).…”

Section: Induction Of Mesangial Cell Tolerance By Macrophage-derived mentioning

confidence: 99%

Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli

Hayakawa

Meng

Hiramatsu

et al. 2006

The Journal of Immunology

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Macrophage-mesangial cell interaction plays a crucial role in the pathogenesis of glomerulonephritis. Activated macrophages trigger mesangial cells to express an array of inflammation-associated genes via activation of NF-κB and AP-1. However, this inflammatory response is often transient and subsides spontaneously. We found that mesangial cells activated by bystander macrophages showed blunted responses of NF-κB to subsequent macrophage exposure. It was associated with sustained levels of IκBβ, but not IκBα. The tolerance observed was reversible and reproduced by conditioned media from activated macrophages (macrophage-conditioned medium (MφCM)). In vivo priming of mesangial cells by activated glomerular macrophages also caused the tolerance of mesangial cells. The macrophage-derived tolerance inducers were heat-labile, and multiple molecules were involved. Among inflammatory cytokines produced by macrophages, TNF-α and IL-1β were able to induce mesangial cell tolerance dose-dependently. The mesangial cell tolerance was also observed in activation of the MAPK-AP-1 pathway; i.e., phosphorylation of ERK, JNK, and p38 MAPK by macrophages was blunted when the cells were pre-exposed to MφCM. Induction of c-fos and c-jun was also abrogated in mesangial cells pre-exposed to MφCM, and the suppression was attenuated by blockade of MAPK activation during the first exposure to MφCM. These data elucidated that mesangial cells, once exposed to macrophages, become insensitive to subsequent activation by macrophages and proinflammatory stimuli. This self defense of glomerular cells may play a role in the resolution of macrophage-mediated, acute glomerulonephritis.

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Transfer of genetically engineered macrophages into the glomerulus

Cited by 25 publications

References 32 publications

Macrophages Transfected with Adenovirus to Express IL-4 Reduce Inflammation in Experimental Glomerulonephritis

Macrophages Transfected with Adenovirus to Express IL-4 Reduce Inflammation in Experimental Glomerulonephritis

Gene transfer into inflamed glomeruli using macrophages transfected with adenovirus

Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli

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