Complement C5 Inhibition Reduces T Cell-Mediated Allograft Vasculopathy Caused by Both Alloantibody and Ischemia Reperfusion Injury in Humanized Mice.
Allograft vasculopathy (AV) is characterized by diffuse stenoses in the vasculature of solid organ transplants. Previously, we developed two humanized models showing that alloantibody and ischemia reperfusion injury (IRI) exacerbated T cell-mediated AV in human arterial xenografts in vivo. Herein we examined a causal role for terminal complement activation in both settings. IRI, in contrast to alloantibody, elicited widespread membrane attack complex (MAC) assembly throughout the vessel wall. Both alloantibody and IRI caused early (24 h) and robust endothelial cell (EC) activation localized to regions of intimal MAC deposition, indicated by increases in nuclear factor kappa B (NF-κB)-inducing kinase, an MAC-dependent activator of noncanonical NF-kB, VCAM-1 expression and Gr-1+ neutrophil infiltration. Endothelial cell activation by alloantibody was inhibited by antimouse C5 mAb, but not by anti-C5a mAb or by control mAb, implicating MAC as the primary target of anti-C5 mAb. Antimouse C5 mAb significantly reduced alloantibody- and IRI-enhanced T cell infiltration and AV-like changes, including neointimal hyperplasia as well as intraluminal thrombosis in a subset of IRI-treated arterial grafts. These results indicate that increased AV lesion formation in response to either alloantibody or IRI is dependent on complement C5 activation and, accordingly, inhibition of this pathway may attenuate AV.
Department of Surgery, Yale School of Medicine, New Haven, CT.
L
L
Qin
Department of Surgery, Yale School of Medicine, New Haven, CT.
G
G
Li
Department of Immunobiology, Yale School of Medicine, New Haven, CT.
N
N
Kirkiles-Smith
Department of Immunobiology, Yale School of Medicine, New Haven, CT.
P
P
Clark
Department of Immunobiology, Yale School of Medicine, New Haven, CT.
C
C
Fang
Alexion Pharmaceuticals Inc., New Haven, CT.
Y
Y
Wang
Alexion Pharmaceuticals Inc., New Haven, CT.
Z-X
ZX
Yu
Alexion Pharmaceuticals Inc., New Haven, CT.
D
D
Devore
Department of Surgery, Yale School of Medicine, New Haven, CT.
G
G
Tellides
Department of Immunobiology, Yale School of Medicine, New Haven, CT.
J S
JS
Pober
Department of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT.
D
D
Jane-Wit
D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002478:Cells, Cultured; D003167:Complement Activation; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications*; D013601:T-Lymphocytes / Q000276:immunology*; D014652:Vascular Diseases / Q000209:etiology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D003182:Complement C5; D007518:Isoantibodies; D016328:NF-kappa B
alloantibody; basic (laboratory) research/science; complement biology; fusion proteins and monoclonal antibodies; immunobiology; immunosuppressant; immunosuppression/immune modulation; ischemia reperfusion injury (IRI); organ transplantation in general; translational research/science; vasculopathy