Ischemia reperfusion injury (IRI) contributes to delayed graft function, inflammation and graft loss. Many components of IRI are ameliorated by nitric oxide (NO) signaling. The endogenous thrombospondin-1 /CD47 system inhibits NO signaling thus exacerbating IRI. Therefore, blocking CD47 and preventing NO inhibition may improve IRI in organ transplantation. We tested this hypothesis in a syngeneic Lewis rat model of kidney transplantation. Donor kidneys were flushed with 50 ug of CD47mAb OX101 or control followed by 6 hr of cold ischemia (CI). After flushing, kidneys were transplanted into recipients. Kidney function, histopathological damage and survival were assessed at 2 and 7 days post transplantation. Immunohistochemical analysis demonstrated that the CD47mAb was localized to the endothelium within the kidney following CI and flush. Two days following transplantation, serum creatinine, BUN and phosphorus levels were markedly elevated in animals that received the IgG-treated kidneys, but were only moderately elevated in the recipients of CD47mAb-treated kidneys. At 7 days post-transplant, values in the recipients of CD47mAb-treated kidneys had returned to sham levels. Similar protection in the recipients of CD47mAb-treated kidneys was observed for additional serum markers of kidney injury, including calbindin, clusterin, osteopontin, tissue inhibitor of metalloproteinase 1, glutathione S transferase alpha and VEGF-A. After 2 days, the kidney grafts from the control group exhibited severe pathological injury, characterized by tubular atrophy, dilatation, cytoplasmic blebbing, tubular cell shedding and coagulative necrosis. In contrast, the CD47 mAb treated group exhibited significantly less injury at both 2 and 7 days. Finally, CD47mAb treatment resulted in significantly greater survival. No recipients of IgG-treated kidneys survived for more than 5 days, while 80% of the recipients of the CD47mAb-treated kidneys survived for 7 days, the duration of the study. These results show that blocking CD47 in the donor organ improves organ preservation, reduces IRI and improves transplant outcomes.

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