title: Complement 5a receptor inhibition improves renal allograft survival.
abstract: Complement activation plays a key role in mediating apoptosis, inflammation, and transplant rejection. In this study, the role of the complement 5a receptor (C5aR) was examined in human renal allografts and in an allogenic mouse model of renal transplant rejection. In human kidney transplants with acute rejection, C5aR expression was increased in renal tissue and in cells infiltrating the tubulointerstitium. Similar findings were observed in mice. When recipient mice were treated once daily with a C5aR antagonist before transplantation, long-term renal allograft survival was markedly improved compared with vehicle-treatment (75 versus 0%), and apoptosis was reduced. Furthermore, treatment with a C5aR antagonist significantly attenuated monocyte/macrophage infiltration, perhaps a result of reduced levels of monocyte chemoattractant protein 1 and the intercellular adhesion molecule 1. In vitro, C5aR antagonism inhibited intercellular adhesion molecule 1 upregulation in primary mouse aortic endothelial cells and reduced adhesion of peripheral blood mononuclear cells. Furthermore, C5aR blockade markedly reduced alloreactive T cell priming. These results demonstrate that C5aR plays an important role in mediating acute kidney allograft rejection, suggesting that pharmaceutical targeting of C5aR may have potential in transplantation medicine.
authors.affiliation: Department of Nephrology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. fgueler@googlemail.com
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.forename: Song
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authors.lastname: Rong
authors.forename: Wilfried
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authors.lastname: Gwinner
authors.forename: Michael
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authors.lastname: Mengel
authors.forename: Verena
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authors.lastname: Bröcker
authors.forename: Sylvia
authors.initials: S
authors.lastname: Schön
authors.forename: Tim Friedrich
authors.initials: TF
authors.lastname: Greten
authors.forename: Heiko
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authors.lastname: Hawlisch
authors.forename: Thomas
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authors.lastname: Polakowski
authors.forename: Karsten
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authors.lastname: Schnatbaum
authors.forename: Jan
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authors.lastname: Menne
authors.forename: Hermann
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authors.lastname: Haller
authors.forename: Nelli
authors.initials: N
authors.lastname: Shushakova