PURPOSE: This study investigated whether the blockade of the CD47 signaling pathway, which is involved in vascular endothelial nitric oxide regulation, reduces ischemia-reperfusion injury (IRI) of renal allografts donated after cardiac death (DCD) in an allogeneic large animal porcine model. METHODS: Renal allografts were subjected to 30 min of warm ischemia time and 3.5 hrs of cold ischemia, and perfused with a humanized anti-CD47 monoclonal antibody (CD47mAb) in the treatment group or HTK solution only in the control group (n=4, respectively). Allograft reperfusion was examined with ICG-based in vivo imaging. Blood and tissue samples were collected, and the animals were euthanized 5 days after transplantation. RESULTS: At the time of reperfusion, in vivo imaging showed that CD47mAb-treated organs had greater and more uniform perfusion. On post-transplant day 3, the treatment group had lower values compared to the control for creatinine (4.4±0.1 vs 8.8±1.7, p<0.001) and blood urea nitrogen (76.7±17.8 vs 112.3±15.9, p<0.01). Histological examination of allograft tissues taken at the end of the experiment showed a significant decrease of the acute tubular injury in the CD47mAb-treated group compared to control (5.7±3.3% vs 43.3±15.2%, p<0.01). Compared to the control group, CD47mAb treatment significantly decreased the mRNA expression of genes related to oxidative injury (sod-1, gpx-1, and txn) and inflammatory response (il-2, il-6, inf-g and tgf-b) in the allografts, as well as MMP2, MMP9, BAX, and caspase-3 (p<0.05, 0.01 or 0.001, respectively). CONCLUSIONS: These data demonstrate that CD47mAb blockade decreases IRI in DCD renal allografts in a large animal model. Its use in human kidney transplants may decrease rates of delayed graft function and improve overall transplant outcomes.

CITATION INFORMATION: Xu M, Banan B, Wang X, Chirumbole D, Rabe B, Garcia-Aroz S, Nayak D, Zhang Z, Jia J, Upadhya G, Gaut J, Manning P, Lin Y, Chapman W. A Humanized Anti-CD47 Monoclonal Antibody Therapy Alleviates Ischemia-Reperfusion Injury of Porcine Renal Allografts Donated After Cardiac Death. Am J Transplant. 2017;17 (suppl 3).

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