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Review
.2019 Oct 4:10:2380.
doi: 10.3389/fimmu.2019.02380. eCollection 2019.

The Role of Complement in Organ Transplantation

Affiliations
Review

The Role of Complement in Organ Transplantation

Monica Grafals et al. Front Immunol..

Abstract

The current immunosuppressive protocols used in transplant recipients have improved short-term outcomes, but long-term allograft failure remains an important clinical problem. Greater understanding of the immunologic mechanisms that cause allograft failure are needed, as well as new treatment strategies for protecting transplanted organs. The complement cascade is an important part of the innate immune system. Studies have shown that complement activation contributes to allograft injury in several clinical settings, including ischemia/reperfusion injury and antibody mediated rejection. Furthermore, the complement system plays critical roles in modulating the responses of T cells and B cells to antigens. Therapeutic complement inhibitors, therefore, may be effective for protecting transplanted organs from several causes of inflammatory injury. Although several anti-complement drugs have shown promise in selected patients, the role of these drugs in transplantation medicine requires further study.

Keywords: alloimmunity; antibody mediated allograft rejection; complement; delayed graft function; therapeutics; transplantation.

Copyright © 2019 Grafals and Thurman.

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Figures

Figure 1
Figure 1
Overview of complement activation. Specific activating molecules engage the classical, lectin, and alternative pathways. Cleavage of C4 and C2 generates C4b2a, the classical and lectin pathway C3 convertases (enzymes that cleave C3). C3 generated by the classical and lectin pathways can combine with factor B (FB), which is then cleaved by factor D (FD), to form C3bBb. C3bBb is the alternative pathway C3 convertase, and can also be generated by spontaneous formation of C3b. The C3 convertases combine with another C3b to form the C5 convertase, which then cleaves C5 into C5b and C5a. C5b combines with C6, C7, C8, and C9 to form C5b-9, or the membrane attack complex. The convertases are depicted in green, and pro-inflammatory molecules generated during complement activation are shown in red.
Figure 2
Figure 2
Complement activation in antibody-mediated rejection. Antibody-mediated rejection is caused by binding of antibodies to human leukocyte antigens (HLA) expressed on endothelial cells of the transplanted organ. The antibodies (referred to as donor specific antibodies, or DSA) activate the classical pathway of complement. Classical pathway activation causes the cleavage of C4, and one of the resultant C4 fragments (C4b) is covalently attached to target surfaces. C4b comprises part of the classical pathway C3 convertase, C4b2a. C3b can become covalently attached to target cells, similar to C4b. A protease called factor I (FI) controls complement activation by cleaving the C4b and C3b molecules, thereby stopping convertase activity. Although they are no longer catalytically active, the C4d and C3dg fragments remain bound to the target cells and can be detected by immunostaining of tissue biopsies.
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