title: Macrophages act as effectors of tissue damage in acute renal allograft rejection.
abstract: BACKGROUND
  Macrophages constitute 38% to 60% of infiltrating cells during acute renal allograft rejection. Their contribution to tissue damage during acute rejection was examined by depleting macrophages in a rat model.
  
  
  METHODS
  Lewis rats underwent bilateral nephrectomy and then received a Dark Agouti renal allograft and liposomal-clodronate, control phosphate-buffered saline liposomes, or saline intravenously (n=7 per group) on days 1 and 3 postsurgery. Grafts were harvested on day 5.
  
  
  RESULTS
  Liposomal-clodronate treatment resulted in a 70% reduction in blood ED1+ monocytes and 60% reduction in intragraft ED1+ macrophages (both P<0.01). Half of all remaining interstitial ED1+ cells were undergoing apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling+/ED1+), and thus functional depletion of more than 75% of macrophages was achieved. Histologic and functional parameters of acute rejection were attenuated: interstitial infiltrate, tubulitis, and glomerulitis (P<0.01); tubular cell apoptosis (P<0.001); tubular cell proliferation (P<0.001); and serum creatinine (P<0.01). Production of inducible nitric oxide synthase by infiltrating cells and urinary nitric oxide excretion was reduced by 90% (P<0.001). In contrast, no reduction in the number of other leukocytes was seen (CD3+, CD4+, CD8+, and natural killer cells). Activation of lymphocytes (CD25+) and production of lymphocyte effector molecules (granzyme B) were unaltered.
  
  
  CONCLUSIONS
  This study demonstrates that macrophages contribute to tissue damage during acute rejection.
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia. matthew.jose@med.monash.edu.au.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Jose
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ikezumi
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Robert C
authors.initials: RC
authors.lastname: Atkins
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Chadban
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002465:Cell Movement; D003165:Complement System Proteins / Q000378:metabolism; D006084:Graft Rejection / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000473:pathology; D008214:Lymphocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D008297:Male; D009393:Nephritis / Q000209:etiology / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D014184:Transplantation, Homologous
chemical_list: D009569:Nitric Oxide; D003165:Complement System Proteins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat