CD47 blockade reduces ischemia-reperfusion injury and improves outcomes in a rat kidney transplant model

Yiing Lin, Pamela T. Manning, Jianluo Jia, Joseph P. Gaut, Zhenyu Xiao, Benjamin J. Capoccia, Chun Cheng Chen, Ronald R. Hiebsch, Gundumi Upadhya, Thalachallour Mohanakumar, William A. Frazier, William C. Chapman

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 ofWisconsin 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. Conclusion. These results provide strong evidence for the use of CD47 antibodyYmediated blockade to reduce IRI and improve organ preservation for renal transplantation.

Original languageEnglish
Pages (from-to)394-401
Number of pages8
JournalTransplantation
Volume98
Issue number4
DOIs
StatePublished - 2014

Keywords

  • Antibody therapy
  • Ischemia-reperfusion injury
  • Kidney transplant
  • Nitric oxide

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