TY - JOUR
T1 - Anti-CD47 monoclonal antibody therapy reduces ischemia-reperfusion injury of renal allografts in a porcine model of donation after cardiac death
AU - Xu, Min
AU - Wang, Xuanchuan
AU - Banan, Babak
AU - Chirumbole, Danielle L.
AU - Garcia-Aroz, Sandra
AU - Balakrishnan, Aparna
AU - Nayak, Deepak K.
AU - Zhang, Zhengyan
AU - Jia, Jianluo
AU - Upadhya, Gundumi A.
AU - Gaut, Joseph P.
AU - Hiebsch, Ronald
AU - Manning, Pamela T.
AU - Wu, Ningying
AU - Lin, Yiing
AU - Chapman, William C.
N1 - Funding Information:
This project was funded in part by the Barnes-Jewish Hospital Foundation Project Award, Transplant Research Support and by the National Institutes of Health grant 5R44DK092078. The content is solely the responsibility of the authors and does necessarily represent the official views of the National Institutes of Health. We thank Tioma Therapeutics, Inc. for providing the CD47mAb and the Digestive Diseases Research Core Centers (DDRCC, NIDDK P30 DK052574) at WUSM for sharing equipment and core facility support. We appreciate the help from NOVADAQ Technologies (Burnaby, BC, Canada) for providing the NIR imaging system used in the study.
Funding Information:
This project was funded in part by the Barnes-Jewish Hospital
Publisher Copyright:
© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2018/4
Y1 - 2018/4
N2 - We investigated whether blockade of the CD47 signaling pathway could reduce ischemia-reperfusion injury (IRI) of renal allografts donated after cardiac death (DCD) in a porcine animal model of transplantation. Renal allografts were subjected to 30 minutes of warm ischemia, 3.5 hours of cold ischemia, and then perfused with a humanized anti-CD47 monoclonal antibody (CD47mAb) in the treatment group or HTK solution in the control group (n = 4/group). The animals were euthanized five days after transplantation. At the time of reperfusion, indocyanine green-based in vivo imaging showed that CD47mAb-treated organs had greater and more uniform reperfusion. On post-transplant days 3-5, the treatment group had lower values compared to the control for creatinine and blood urea nitrogen. Histological examination of allograft tissues showed a significant decrease of acute tubular injury in the CD47mAb-treated group compared to control. Compared to the control group, CD47mAb treatment significantly decreased genes expression related to oxidative stress (sod-1, gpx-1, and txn), the inflammatory response (il-2, il-6, inf-g, and tgf-b), as well as reduced protein levels of BAX, Caspase-3, MMP2, and MMP9. These data demonstrate that CD47mAb blockade decreases IRI and subsequent tissue injury in DCD renal allografts in a large animal transplant model.
AB - We investigated whether blockade of the CD47 signaling pathway could reduce ischemia-reperfusion injury (IRI) of renal allografts donated after cardiac death (DCD) in a porcine animal model of transplantation. Renal allografts were subjected to 30 minutes of warm ischemia, 3.5 hours of cold ischemia, and then perfused with a humanized anti-CD47 monoclonal antibody (CD47mAb) in the treatment group or HTK solution in the control group (n = 4/group). The animals were euthanized five days after transplantation. At the time of reperfusion, indocyanine green-based in vivo imaging showed that CD47mAb-treated organs had greater and more uniform reperfusion. On post-transplant days 3-5, the treatment group had lower values compared to the control for creatinine and blood urea nitrogen. Histological examination of allograft tissues showed a significant decrease of acute tubular injury in the CD47mAb-treated group compared to control. Compared to the control group, CD47mAb treatment significantly decreased genes expression related to oxidative stress (sod-1, gpx-1, and txn), the inflammatory response (il-2, il-6, inf-g, and tgf-b), as well as reduced protein levels of BAX, Caspase-3, MMP2, and MMP9. These data demonstrate that CD47mAb blockade decreases IRI and subsequent tissue injury in DCD renal allografts in a large animal transplant model.
KW - basic (laboratory) research/science
KW - donors and donation: deceased
KW - kidney (allograft) function/dysfunction
KW - kidney transplantation/nephrology
KW - translational research/science
UR - http://www.scopus.com/inward/record.url?scp=85036594089&partnerID=8YFLogxK
U2 - 10.1111/ajt.14567
DO - 10.1111/ajt.14567
M3 - Article
C2 - 29087049
AN - SCOPUS:85036594089
SN - 1600-6135
VL - 18
SP - 855
EP - 867
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 4
ER -