The role of complement in antibody-mediated rejection in kidney transplantation

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

M. D. Stegall, M. F. Chedid and L. D. Cornell contributed equally to researching data for the article, discussions of the content, writing the article and review and/or editing of the

manuscript before submission.

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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