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Antibody-Mediated Transplant Rejection the Complement System The Complement System and Antibody-Mediated Transplant Rejection Erik Stites, Moglie Le Quintrec and Joshua M. Thurman This information is current as J Immunol 2015; 195:5525-5531; ; of September 27, 2021. doi: 10.4049/jimmunol.1501686 http://www.jimmunol.org/content/195/12/5525 Downloaded from References This article cites 106 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/195/12/5525.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology The Complement System and Antibody-Mediated Transplant Rejection Erik Stites,* Moglie Le Quintrec,† and Joshua M. Thurman* Complement activation is an important cause of tissue activate the classical pathway of complement (Fig. 1A). injury in patients with Ab-mediated rejection (AMR) of Although protocols for desensitizing patients to the ABO transplanted organs. Complement activation triggers a Ags have shown some promise, ABO-incompatible trans- strong inflammatory response, and it also generates plantation is not widely performed; thus, class I and class II tissue-bound and soluble fragments that are clinically HLA are the most common targets of DSA. Preformed DSA useful markers of inflammation. The detection of com- can exist prior to transplant due to exposure to the Ags though plement proteins deposited within transplanted tissues pregnancy, blood transfusions, or previous transplants. De has become an indispensible biomarker of AMR, and novo DSA can develop after transplantation. Recipients can Downloaded from several assays have recently been developed to measure also generate a humoral response to non-HLA (11, 12). complement activation by Abs reactive to specific donor Patel and Terasaki (13) first observed the high incidence of HLA expressed within the transplant. Complement immediate graft failure due to widespread capillary throm- bosis and necrosis in sensitized recipients .40 y ago. The inhibitors have entered clinical use and have shown authors assessed preformed DSA by mixing recipient sera efficacy for the treatment of AMR. New methods of with donor lymphocytes. This method became known as the http://www.jimmunol.org/ detecting complement activation within transplanted complement-dependent cytotoxicity (CDC) crossmatch and organs will improve our ability to diagnose and monitor was the gold standard for assessing donor/recipient com- AMR, and they will also help guide the use of comple- patibility for decades (14). The rapid occurrence of rejection ment inhibitory drugs. The Journal of Immunology, and poor outcomes of transplantation across a positive CDC 2015, 195: 5525–5531. crossmatch highlighted the importance of preformed Abs and complement activation in hyperacute rejection and graft loss. ransplantation is the best treatment for end-stage Prior to the early 1990s, acute rejection events were widely by guest on September 27, 2021 disease of the kidneys, heart, liver, or lungs. Acute thought to be primarily due to T cell–mediated immunity T rejection events are associated with worse graft out- (15). However, several studies later showed that acute rejec- comes, and Ab-mediated rejection (AMR) imparts a poorer tion in renal transplant recipients who developed DSA after prognosis compared with cellular rejection (1–3). AMR is now transplant was clinically and pathologically distinct from re- the leading cause of late graft failure in kidney transplant jection events in patients without DSA. Rejection events with recipients (4–7). Complement activation within allografts is DSA were associated with swollen and detached endothelial caused by ischemia at the time of transplantation, and also by cells, glomerulitis (inflammation of glomerular capillaries), Ig bound to Ags within the allograft during acute and chronic small-vessel vasculitis, neutrophil infiltration, and vascular AMR (8). occlusion. Acute rejection with DSA was also more severe and Ab-mediated rejection. AMR is a clinical and histopathologic resulted in worse outcomes. Interestingly, deposited Ig was diagnosis based on detection of allograft dysfunction with rarely seen in the allografts (16, 17). A similar pattern of evidence of endothelial inflammation, and it is mediated by endothelial inflammation is also seen in cardiac and lung circulating Abs directed against donor Ags in the allograft (9). transplants with DSA and Ab-mediated injury (18, 19). Allelic variation in the genes for ABO blood group Ags and The link between complement and rejection was solidified HLA cause these proteins to be recognized as foreign by the when Feucht et al. (20, 21) demonstrated the complement recipient’s immune system (10). Recipients of organs that are split product C4d in transplant biopsies, implicating the mismatched at these loci can develop Abs (referred to as classical complement pathway in acute and chronic rejection. donor-specific Abs, or DSA) that bind these Ags on the This landmark observation revealed that C4d is a durable surface of endothelial cells in the microvasculature and biomarker of AMR. These and subsequent, corroborating *Department of Medicine, University of Colorado School of Medicine, Aurora, CO of Medicine, B-115, 1775 Aurora Court, M20-3103, Aurora, CO 80045. E-mail ad- 80045; and †Department of Nephrology and Renal Transplantation, Lapeyronie Hos- dress: [email protected] pital, 34295 Montpellier Cedex 5, France Abbreviations used in this article: AMR, Ab-mediated rejection; CDC, complement- Received for publication July 27, 2015. Accepted for publication September 11, 2015. dependent cytotoxicity; DSA, donor-specific Ab; MAC, membrane attack complex. This work was supported in part by National Institutes of Health Grant R01 DK076690 Ó (to J.M.T.). Copyright 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 Address correspondence and reprint requests to Dr. Joshua M. Thurman, Division of Nephrology and Hypertension, Department of Medicine, University of Colorado School www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501686 5526 BRIEF REVIEWS: COMPLEMENT AND REJECTION is not expressed on endothelial cells constitutively but has been shown to be inducible in vitro (30). The alternative pathway amplifies complement activation, even when activa- tion is initially triggered by the classical pathway, and this process is limited by a soluble protein called factor H and also by a cell surface regulator called complement receptor of the Ig superfamily (Fig. 1A) (31). Efficient complement regula- tion limits downstream complement activation (32, 33), and it is possible to have abundant C4 fragment deposition on a surface in the absence of detectable C3 (34). The extent of complement activation by immune complexes is determined by multiple factors, including the isotype of the Ab, the abundance of the target Ag and density of Ig, and the local concentration of complement regulatory proteins. Prior FIGURE 1. Complement activation in AMR. (A) The classical pathway of exposure to the target Ags and treatment with immunosup- complement is activated when C1q binds to IgG clustered on endothelial pressive drugs affects Ab generation. In vitro studies have HLA. Each C1q deposits multiple C4 molecules on target surfaces. Efficient shown that expression of HLA and complement regulator complement regulation stops the reaction before C3 molecules are deposited. proteins on endothelial cells is altered by inflammatory stimuli Downloaded from In contrast, complete complement activation results in covalent fixation of (35). Thus, Ab-mediated allograft injury is not simply a multiple C3 fragments to the target tissue. This process is augmented by the function of the presence of DSA in serum, but it is influenced alternative pathway amplification loop, although several regulatory proteins control the alternative pathway. Complement regulatory proteins metabolize by numerous local and systemic factors. the C3b to iC3b and then to C3dg. (B) Complete complement activation generates several biologically active products, including C3a, C3b, C5a, and Mechanisms of complement-mediated endothelial injury C5b-9. C4bp, C4 binding protein; DAF, decay-accelerating factor; fH, factor Complement activation produces several biologically active http://www.jimmunol.org/ H; fI, factor I; MCP, membrane cofactor protein. fragments (Fig. 1B). C3b is covalently fixed to surfaces and acts as an opsonin. C5b-9 (the membrane attack complex studies led to the development of consensus diagnostic criteria [MAC]) forms pores through the outer membrane of cells and in renal allografts for acute AMR at the 2001 Banff Confer- can cause cellular activation, signaling, cell lysis, and possibly ence on
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