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

      Molecular Therapy

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

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          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.

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