CD47 Blockade Reduces Ischemia-reperfusion Injury and Improves Outcomes in a Rat Kidney Transplant Model

Overview

Journal Transplantation

Specialty General Surgery

Date 2014 Jul 2

PMID 24983310

Citations 19

Authors

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

Affiliations

Soon will be listed here.

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.

Conclusion: These results provide strong evidence for the use of CD47 antibody-mediated blockade to reduce IRI and improve organ preservation for renal transplantation.

Citing Articles

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CD47 is Required for Mesenchymal Progenitor Proliferation and Fracture Repair.

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References

Yarlagadda S, Coca S, Formica Jr R, Poggio E, Parikh C . Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant. 2008; 24(3):1039-47. DOI: 10.1093/ndt/gfn667. View

Isenberg J, Romeo M, Abu-Asab M, Tsokos M, Oldenborg A, Pappan L . Increasing survival of ischemic tissue by targeting CD47. Circ Res. 2007; 100(5):712-20. DOI: 10.1161/01.RES.0000259579.35787.4e. View

Dragun D, Hoff U, Park J, Qun Y, Schneider W, Luft F . Prolonged cold preservation augments vascular injury independent of renal transplant immunogenicity and function. Kidney Int. 2001; 60(3):1173-81. DOI: 10.1046/j.1523-1755.2001.0600031173.x. View

Inglott F, Mathie R . Nitric oxide and hepatic ischemia-reperfusion injury. Hepatogastroenterology. 2001; 47(36):1722-5. View

Hines I, Harada H, Flores S, Gao B, McCord J, Grisham M . Endothelial nitric oxide synthase protects the post-ischemic liver: potential interactions with superoxide. Biomed Pharmacother. 2005; 59(4):183-9. DOI: 10.1016/j.biopha.2005.03.011. View

Levitsky J, Salomon D, Abecassis M, Langfelder P, Horvath S, Friedewald J . Clinical and plasma proteomic markers correlating with chronic kidney disease after liver transplantation. Am J Transplant. 2011; 11(9):1972-8. PMC: 3166389. DOI: 10.1111/j.1600-6143.2011.03669.x. View

Requiao-Moura L, Durao M, Tonato E, Matos A, Ozaki K, Camara N . Effects of ischemia and reperfusion injury on long-term graft function. Transplant Proc. 2011; 43(1):70-3. DOI: 10.1016/j.transproceed.2010.12.012. View

Isenberg J, Pappan L, Romeo M, Abu-Asab M, Tsokos M, Wink D . Blockade of thrombospondin-1-CD47 interactions prevents necrosis of full thickness skin grafts. Ann Surg. 2007; 247(1):180-90. PMC: 2432017. DOI: 10.1097/SLA.0b013e31815685dc. View

Bauer P, Bauer E, Rogers N, Yao M, Feijoo-Cuaresma M, Pilewski J . Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1. Cardiovasc Res. 2012; 93(4):682-93. PMC: 3291089. DOI: 10.1093/cvr/cvr356. View

10.

Irish W, Ilsley J, Schnitzler M, Feng S, Brennan D . A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation. Am J Transplant. 2010; 10(10):2279-86. DOI: 10.1111/j.1600-6143.2010.03179.x. View

11.

Siedlecki A, Jin X, Thomas W, Hruska K, Muslin A . RGS4, a GTPase activator, improves renal function in ischemia-reperfusion injury. Kidney Int. 2011; 80(3):263-71. PMC: 3221244. DOI: 10.1038/ki.2011.63. View

12.

Maxhimer J, Shih H, Isenberg J, Miller T, Roberts D . Thrombospondin-1/CD47 blockade following ischemia-reperfusion injury is tissue protective. Plast Reconstr Surg. 2009; 124(6):1880-1889. PMC: 2794041. DOI: 10.1097/PRS.0b013e3181bceec3. View

13.

Quiroga I, McShane P, Koo D, Gray D, Friend P, Fuggle S . Major effects of delayed graft function and cold ischaemia time on renal allograft survival. Nephrol Dial Transplant. 2006; 21(6):1689-96. DOI: 10.1093/ndt/gfl042. View

14.

Isenberg J, Maxhimer J, Powers P, Tsokos M, Frazier W, Roberts D . Treatment of liver ischemia-reperfusion injury by limiting thrombospondin-1/CD47 signaling. Surgery. 2008; 144(5):752-61. PMC: 2635486. DOI: 10.1016/j.surg.2008.07.009. View

15.

Rogers N, Thomson A, Isenberg J . Activation of parenchymal CD47 promotes renal ischemia-reperfusion injury. J Am Soc Nephrol. 2012; 23(9):1538-50. PMC: 3431420. DOI: 10.1681/ASN.2012020137. View

16.

Legrand M, Mik E, Johannes T, Payen D, Ince C . Renal hypoxia and dysoxia after reperfusion of the ischemic kidney. Mol Med. 2008; 14(7-8):502-16. PMC: 2386087. DOI: 10.2119/2008-00006.Legrand. View

17.

Suda T, Mora B, DOvidio F, Cooper J, Hiratsuka M, Zhang W . In vivo adenovirus-mediated endothelial nitric oxide synthase gene transfer ameliorates lung allograft ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2000; 119(2):297-304. DOI: 10.1016/S0022-5223(00)70185-1. View

18.

Abe Y, Hines I, Zibari G, Grisham M . Hepatocellular protection by nitric oxide or nitrite in ischemia and reperfusion injury. Arch Biochem Biophys. 2008; 484(2):232-7. PMC: 2694442. DOI: 10.1016/j.abb.2008.10.006. View

19.

Ho J, Dart A, Rigatto C . Proteomics in acute kidney injury--current status and future promise. Pediatr Nephrol. 2013; 29(2):163-71. DOI: 10.1007/s00467-013-2415-x. View

20.

Schumacher M, Van Vliet B, Ferrari P . Kidney transplantation in rats: an appraisal of surgical techniques and outcome. Microsurgery. 2003; 23(4):387-94. DOI: 10.1002/micr.10139. View