title: Depletion of cells of monocyte lineage prevents loss of renal microvasculature in murine kidney transplantation.
abstract: BACKGROUND
  Acute rejection increases the risk of late renal allograft loss with tubular atrophy, interstitial fibrosis, and microvascular rarefaction. Evidence supports a role for macrophages in promoting allograft injury, but the pathogenic mechanisms are unclear. Using a model of acute rejection, we sought evidence of macrophage-mediated endothelial cell cytotoxicity leading to loss of the renal microvasculature.
  
  
  METHODS
  We used a transgenic conditional ablation strategy to deplete circulating monocytes and infiltrating renal macrophages after kidney transplantation. CD11b-DTR mice (FVB/nj strain) are transgenic for the human diphtheria toxin receptor gene under the control of the CD11b promoter. Administration of diphtheria toxin results in rapid ablation of circulating monocytes and resident/infiltrating renal macrophages. Transplants were performed between fully mismatched strains (Balb/c donor into control nontransgenic FVB/nj recipient; allograft group), between FVB/nj littermates (isograft group), and from Balb/c donors into CD11b-DTR mice (DT-treated group). Diphtheria toxin was administered at days 3 and 5, and the effect of monocyte/macrophage depletion on changes in renal microvasculature was determined at day 7.
  
  
  RESULTS
  Conditional monocyte and macrophage ablation effectively depleted infiltrating macrophages in murine renal allografts at day 7. Macrophage ablation reduced histologic features of rejection (arteritis, tubulitis) and the accompanying rarefaction of peritubular capillaries at 7 days. The identification of macrophages immunopositive for inducible nitric oxide synthase implicated nitric oxide generation as a possible mechanism of endothelial cell cytotoxicity.
  
  
  CONCLUSIONS
  These data indicate a significant role for macrophages in causing acute rejection-related tissue injury that is, at least in part, targeted to the microcirculation.
authors.affiliation: Phagocyte Laboratory, Centre for Inflammation Research, Queen's Medical Research Institute, Little France Crescent, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: Qi
authors.forename: A
authors.initials: A
authors.lastname: Adair
authors.forename: D
authors.initials: D
authors.lastname: Ferenbach
authors.forename: D G
authors.initials: DG
authors.lastname: Vass
authors.forename: K J
authors.initials: KJ
authors.lastname: Mylonas
authors.forename: T
authors.initials: T
authors.lastname: Kipari
authors.forename: M
authors.initials: M
authors.lastname: Clay
authors.forename: D C
authors.initials: DC
authors.lastname: Kluth
authors.forename: J
authors.initials: J
authors.lastname: Hughes
authors.forename: L P
authors.initials: LP
authors.lastname: Marson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects; D004167:Diphtheria Toxin / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007668:Kidney / Q000098:blood supply*; D016030:Kidney Transplantation / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D055806:Microvessels / Q000473:pathology*; D023421:Models, Animal; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011042:Poisons / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D039481:CD11b Antigen; D004167:Diphtheria Toxin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011042:Poisons; D018664:Interleukin-12; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II