Bone-marrow-derived macrophages genetically modified to produce IL-10 reduce injury in experimental glomerulonephritis.
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.
Wilson
Heather M
HM
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom. h.m.wilson@abdn.ac.uk
Stewart
Keith N
KN
Brown
Paul A J
PA
Anegon
Ignacio
I
Chettibi
Salah
S
Rees
Andrew J
AJ
Kluth
David C
DC
D000419:Albuminuria / Q000276:immunology / Q000628:therapy; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D007668:Kidney / Q000473:pathology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma