Over the past decade, several studies have suggested that the complement system has an active role in both acute and chronic allograft rejection. These studies have been facilitated by improved techniques to detect antibody-mediated organ rejection, including immunohistological staining for C4d deposition in the allograft and solid-phase assays that identify donor-specific alloantibodies (DSAs) in the serum of transplant recipients. Studies with eculizumab, a humanized monoclonal antibody directed against complement component C5, have shown that activation of the terminal complement pathway is necessary for the development of acute antibody-mediated rejection in recipients of living-donor kidney allografts who have high levels of DSAs. The extent to which complement activation drives chronic antibody-mediated injury leading to organ rejection is less clear. In chronic antibody-mediated injury, early complement activation might facilitate chemotaxis of inflammatory cells into the allograft in a process that later becomes somewhat independent of DSA levels and complement factors. In this Review, we discuss the different roles that the complement system might have in antibody-mediated allograft rejection, with specific emphasis on renal transplantation.
Activation of the complement cascade by donor-specific alloantibodies (DSAs) might be the primary mechanism of acute antibody-mediated rejection (AMR) in sensitized kidney transplant recipients
Complement activation might cause injury by enhancing cellular infiltration and inflammation or by directly damaging the allograft
Blockade of complement component C5 with eculizumab reduces the incidence of early AMR in sensitized renal transplant recipients
The role of complement activation in chronic antibody-mediated injury is not yet clear: complement probably initiates intragraft inflammation, but might not be necessary for maintaining it.
Complement components might modulate T-cell activity and adaptive immune responses involved in allograft rejection
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M. D. Stegall and L. D. Cornell have received grant support from Alexion Pharmaceuticals. M. D. Stegall has also received grant support from Millennium Pharmaceuticals. M. F. Chedid declares no competing interests.
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Stegall, M., Chedid, M. & Cornell, L. The role of complement in antibody-mediated rejection in kidney transplantation. Nat Rev Nephrol 8, 670–678 (2012). https://doi.org/10.1038/nrneph.2012.212
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