title: Attenuation of Ischemia-Reperfusion Injury and Improvement of Survival in Recipients of Steatotic Rat Livers Using CD47 Monoclonal Antibody.
abstract: Despite the efficacy of orthotopic liver transplantation in the treatment of end-stage liver diseases, its therapeutic utility is severely limited by the availability of donor organs. The ability to rehabilitate marginal organs, such as steatotic allografts, has the potential to address some of the supply limitations of available organs for transplantation. Steatotic livers are more susceptible to ischemia-reperfusion injury (IRI), which is exacerbated by the thrombospondin-1/CD47 pathway through inhibition of nitric oxide signaling. We postulated that CD47 blockade with a monoclonal antibody specific to CD47, clone 400 (CD47mAb400) may reduce the extent of IRI in steatotic liver allografts.
  
  
  
  Orthotopic liver transplantation was performed using steatotic liver grafts from Zucker rats transplanted into lean recipients. Control IgG or the CD47mAb400 was administered to the donor livers at procurement. Serum transaminases, histological changes, and animal survival were assessed. Hepatocellular damage, oxidative and nitrosative stress, and inflammation were also quantified.
  
  
  
  Administration of CD47mAb400 to donor livers increased recipient survival and resulted in significant reduction of serum transaminases, bilirubin, triphosphate nick-end labeling staining, caspase-3 activity, oxidative and nitrosative stresses, and proinflammatory cytokine expression of TNF-α, IL-6 and IL-1β.
  
  
  
  We conclude that administration of CD47mAb400 to donor grafts may reduce IRI through CD47 blockade to result in improved function of steatotic liver allografts and increased survival of recipients and represent a novel strategy to allow the use of livers with higher levels of steatosis.
authors.affiliation: 1 Department of Surgery, Washington University School of Medicine, St. Louis, MO.2 Vasculox, Inc., St. Louis, MO.3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.4 Departments of Biochemistry and Molecular Biophysics, Cell Biology, and Physiology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Xiao
authors.forename: Babak
authors.initials: B
authors.lastname: Banan
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Jianluo
authors.initials: J
authors.lastname: Jia
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Manning
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Hiebsch
authors.forename: Muthukumar
authors.initials: M
authors.lastname: Gunasekaran
authors.forename: Gundumi A
authors.initials: GA
authors.lastname: Upadhya
authors.forename: William A
authors.initials: WA
authors.lastname: Frazier
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
authors.forename: Yiing
authors.initials: Y
authors.lastname: Lin
authors.forename: William C
authors.initials: WC
authors.lastname: Chapman
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D051928:CD47 Antigen / Q000276:immunology*; D002465:Cell Movement; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000276:immunology* / Q000601:surgery; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation; D008099:Liver / Q000473:pathology / Q000601:surgery; D016031:Liver Transplantation; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction; D000637:Transaminases / Q000097:blood; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D000637:Transaminases