title: CD47 blockade reduces ischemia-reperfusion injury and improves outcomes in a rat kidney transplant model.
abstract: BACKGROUND
  Ischemia-reperfusion injury (IRI) significantly contributes to delayed graft function and inflammation, leading to graft loss. Ischemia-reperfusion injury is exacerbated by the thrombospondin-1-CD47 system through inhibition of nitric oxide signaling. We postulate that CD47 blockade and prevention of nitric oxide inhibition reduce IRI in organ transplantation.
  
  
  METHODS
  We used a syngeneic rat renal transplantation model of IRI with bilaterally nephrectomized recipients to evaluate the effect of a CD47 monoclonal antibody (CD47mAb) on IRI. Donor kidneys were flushed with CD47mAb OX101 or an isotype-matched control immunoglobulin and stored at 4°C in University of Wisconsin solution for 6 hr before transplantation.
  
  
  RESULTS
  CD47mAb perfusion of donor kidneys resulted in marked improvement in posttransplant survival, lower levels of serum creatinine, blood urea nitrogen, phosphorus and magnesium, and less histological evidence of injury. In contrast, control groups did not survive more than 5 days, had increased biochemical indicators of renal injury, and exhibited severe pathological injury with tubular atrophy and necrosis. Recipients of CD47mAb-treated kidneys showed decreased levels of plasma biomarkers of renal injury including Cystatin C, Osteopontin, Tissue Inhibitor of Metalloproteinases-1 (TIMP1), β2-Microglobulin, Vascular Endothelial Growth Factor A (VEGF-A), and clusterin compared to the control group. Furthermore, laser Doppler assessment showed higher renal blood flow in the CD47mAb-treated kidneys.
  
  
  CONCLUSIONS
  These results provide strong evidence for the use of CD47 antibody-mediated blockade to reduce IRI and improve organ preservation for renal transplantation.
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. 5 Address correspondence to: William C. Chapman, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8109, St. Louis, MO 63110.
authors.forename: Yiing
authors.initials: Y
authors.lastname: Lin
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Manning
authors.forename: Jianluo
authors.initials: J
authors.lastname: Jia
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Gaut
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Xiao
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Capoccia
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Chen
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Hiebsch
authors.forename: Gundumi
authors.initials: G
authors.lastname: Upadhya
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
authors.forename: William A
authors.initials: WA
authors.lastname: Frazier
authors.forename: William C
authors.initials: WC
authors.lastname: Chapman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D051928:CD47 Antigen / Q000276:immunology / Q000502:physiology*; D006085:Graft Survival; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; C584934:CD47 protein, rat