Bone-marrow-derived macrophages genetically modified to produce IL-10 reduce injury in experimental glomerulonephritis.

Heather M Wilson, Keith Nicol Stewart, Paul Anthony James Brown, I. Anegon, Salah Chettibi, Andrew Jackson Rees, D. C. Kluth

Research output: Contribution to journalArticle

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Abstract

Macrophages are intimately involved in the development of immune-mediated inflammation, including glomerulonephritis. We have transduced primary cultures of macrophages to express IL-10 and tested the ability of these cells to control rat nephrotoxic nephritis (NTN), a model of human glomerulonephritis. Ad-IL-10-transduced bone-marrow-derived macrophages (BMDM) produced large amounts of IL-10 in culture, and their TNF-alpha production was decreased in response to interferon-gamma and LPS. Transduced macrophages were injected into the renal artery of rats, 6 h after the induction of NTN, where they localized efficiently to inflamed rat glomeruli. Delivery of IL-10-expressing macrophages to nephritic rats produced a marked reduction in albuminuria compared with unmodified NTN or injection of Ad-null-transduced BMDM. IL-10 treatment decreased the number of glomerular ED1- and ED3-positive cells, MHC class 11 expression, and the number of fibrinoid lesions. Interestingly, anti-inflammatory changes in the Ad-IL10-injected kidney were mirrored by changes in the contralateral kidney. These results highlight that Ad-IL-10-transduced macrophages infiltrate inflamed glomeruli and reduce the severity of glomerular inflammation, emphasizing the value of local delivery of genetically modified macrophages in the manipulation of inflammatory disease.

Original languageEnglish
Pages (from-to)710-717
Number of pages8
JournalMolecular Therapy
Volume6
DOIs
Publication statusPublished - 2002

Keywords

  • macrophage
  • gene therapy
  • IL-10
  • nephrotoxic nephritis
  • inflammation
  • autoimmunity
  • adenovirus
  • contralateral effect
  • COLLAGEN-INDUCED ARTHRITIS
  • CRESCENTIC GLOMERULONEPHRITIS
  • GENE-TRANSFER
  • DENDRITIC CELLS
  • RABBIT KNEES
  • VIRAL IL-10
  • T-CELLS
  • INTERLEUKIN-10
  • DISEASE
  • EXPRESSION

Cite this

Bone-marrow-derived macrophages genetically modified to produce IL-10 reduce injury in experimental glomerulonephritis. / Wilson, Heather M; Stewart, Keith Nicol; Brown, Paul Anthony James; Anegon, I.; Chettibi, Salah; Rees, Andrew Jackson; Kluth, D. C.

In: Molecular Therapy, Vol. 6, 2002, p. 710-717.

Research output: Contribution to journalArticle

Wilson, Heather M ; Stewart, Keith Nicol ; Brown, Paul Anthony James ; Anegon, I. ; Chettibi, Salah ; Rees, Andrew Jackson ; Kluth, D. C. / Bone-marrow-derived macrophages genetically modified to produce IL-10 reduce injury in experimental glomerulonephritis. In: Molecular Therapy. 2002 ; Vol. 6. pp. 710-717.
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abstract = "Macrophages are intimately involved in the development of immune-mediated inflammation, including glomerulonephritis. We have transduced primary cultures of macrophages to express IL-10 and tested the ability of these cells to control rat nephrotoxic nephritis (NTN), a model of human glomerulonephritis. Ad-IL-10-transduced bone-marrow-derived macrophages (BMDM) produced large amounts of IL-10 in culture, and their TNF-alpha production was decreased in response to interferon-gamma and LPS. Transduced macrophages were injected into the renal artery of rats, 6 h after the induction of NTN, where they localized efficiently to inflamed rat glomeruli. Delivery of IL-10-expressing macrophages to nephritic rats produced a marked reduction in albuminuria compared with unmodified NTN or injection of Ad-null-transduced BMDM. IL-10 treatment decreased the number of glomerular ED1- and ED3-positive cells, MHC class 11 expression, and the number of fibrinoid lesions. Interestingly, anti-inflammatory changes in the Ad-IL10-injected kidney were mirrored by changes in the contralateral kidney. These results highlight that Ad-IL-10-transduced macrophages infiltrate inflamed glomeruli and reduce the severity of glomerular inflammation, emphasizing the value of local delivery of genetically modified macrophages in the manipulation of inflammatory disease.",
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AB - Macrophages are intimately involved in the development of immune-mediated inflammation, including glomerulonephritis. We have transduced primary cultures of macrophages to express IL-10 and tested the ability of these cells to control rat nephrotoxic nephritis (NTN), a model of human glomerulonephritis. Ad-IL-10-transduced bone-marrow-derived macrophages (BMDM) produced large amounts of IL-10 in culture, and their TNF-alpha production was decreased in response to interferon-gamma and LPS. Transduced macrophages were injected into the renal artery of rats, 6 h after the induction of NTN, where they localized efficiently to inflamed rat glomeruli. Delivery of IL-10-expressing macrophages to nephritic rats produced a marked reduction in albuminuria compared with unmodified NTN or injection of Ad-null-transduced BMDM. IL-10 treatment decreased the number of glomerular ED1- and ED3-positive cells, MHC class 11 expression, and the number of fibrinoid lesions. Interestingly, anti-inflammatory changes in the Ad-IL10-injected kidney were mirrored by changes in the contralateral kidney. These results highlight that Ad-IL-10-transduced macrophages infiltrate inflamed glomeruli and reduce the severity of glomerular inflammation, emphasizing the value of local delivery of genetically modified macrophages in the manipulation of inflammatory disease.

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