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

Mol Ther. 2002 Dec;6(6):710-7. doi: 10.1006/mthe.2002.0802.

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 II expression, and the number of fibrinoid lesions. Interestingly, anti-inflammatory changes in the Ad-IL-10-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / immunology
  • Albuminuria / therapy
  • Animals
  • Bone Marrow Cells / cytology*
  • Cell- and Tissue-Based Therapy / methods*
  • Glomerulonephritis / genetics*
  • Glomerulonephritis / immunology
  • Glomerulonephritis / pathology
  • Glomerulonephritis / therapy*
  • Immunotherapy / methods
  • Interferon-gamma / metabolism
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Interleukin-10 / therapeutic use
  • Kidney / pathology
  • Macrophages / cytology*
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages / transplantation
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Transduction, Genetic
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma