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

ABSTRACT 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. KEY POINTS * 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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support SIMILAR CONTENT BEING VIEWED BY OTHERS THE ROLE OF COMPLEMENT IN KIDNEY DISEASE Article 21 September 2023 C3 COMPLEMENT INHIBITION PREVENTS ANTIBODY-MEDIATED REJECTION AND PROLONGS

RENAL ALLOGRAFT SURVIVAL IN SENSITIZED NON-HUMAN PRIMATES Article Open access 15 September 2021 TRANSLATING B CELL IMMUNOLOGY TO THE TREATMENT OF ANTIBODY-MEDIATED ALLOGRAFT REJECTION

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INFORMATION AUTHORS AND AFFILIATIONS * Department of Surgery, Division of Transplantation Surgery and von Liebig Transplant Center, 200 First Street SW, Mayo Clinic, Rochester, 55905, MN,

USA Mark D. Stegall & Marcio F. Chedid * Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, 200 First Street SW, Mayo Clinic, Rochester, 55905, MN, USA Lynn

D. Cornell Authors * Mark D. Stegall View author publications You can also search for this author inPubMed Google Scholar * Marcio F. Chedid View author publications You can also search for

this author inPubMed Google Scholar * Lynn D. Cornell View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS 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.

CORRESPONDING AUTHOR Correspondence to Mark D. Stegall. ETHICS DECLARATIONS COMPETING INTERESTS 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Stegall, M., Chedid, M. & Cornell, L. The role of complement in antibody-mediated rejection in kidney transplantation. _Nat Rev Nephrol_ 8, 670–678 (2012).

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