The and -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

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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 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 . This method became known as the http://www.jimmunol.org/ detecting complement activation within transplanted complement-dependent (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 –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 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 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, 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 (10). Recipients of organs that are split product C4d in transplant , 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 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 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 . 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 Allograft Pathology (22), and for chronic, active proliferation (36). MAC on the surface of endothelial cells AMR at the 2007 Banff Conference (9). These criteria in- rapidly induces activation of the noncanonical pathway of cluded detection of DSA in serum and C4d in tissues as part NF-kB, which then induces the expression of several of the diagnosis of renal AMR, and similar criteria have been proinflammatory proteins, including IL-6, E-selectin, and by guest on September 27, 2021 proposed for monitoring cardiac AMR (23). VCAM-1 (37). Although ion flux through the MAC can activate endothelial cells, clathrin-mediated endocytosis of the Classical pathway activation by immune complexes MAC from the cell surface was also shown to activate NF-kB Classical pathway activation is initiated when plasma C1q via stabilization of NF-kB–inducing kinase on the surface of binds to the Fc segments of IgM and IgG (24). The relative early endosomes (38). ability of human Ig to activate the classical pathway is IgM . C3a and C5a signal through G protein–coupled receptors IgG3 . IgG1 . IgG2 ..IgG4 (25). Although the C1q expressed on a wide variety of cells, including hematopoietic, binding sites on free IgG are ordinarily exposed, the relative endothelial, and epithelial cells (39). These protein fragments, ∼ affinity of C1q for a single IgG is low (the Kd is 100 mM) referred to as anaphylatoxins, are potent inducers of inflam- (26, 27). C1q is hexameric, however, and when IgG is ag- mation. Signaling through the C5a receptor on endothelial gregated on a target surface C1q can bind multiple IgGs, cells causes the release of heparan sulfate from the cell surface greatly increasing its affinity (∼10 nM) (26). The affinity of (40), and it amplifies production of inflammatory chemokines C1q for IgG is even greater when the Fc regions of IgG are when the cells are also exposed to other (41). C5a packed in a hexamer conformation, leading to effective clas- also directly triggers the release of preformed von Willebrand sical pathway activation (27). Thus, Ab isotype, Ag density, factor from endothelial cells (42). and conformation of aggregated IgG all affect C1q binding Although the complement system is often regarded as a affinity and classical pathway activation. downstream effector system for Ab-mediated injury, com- Complement regulatory proteins also affect the degree of plement activation also promotes the adaptive immune re- complement activation (Fig. 1A). C4-binding protein is a sponse. Several studies have shown that complement activation soluble regulatory protein that inactivates C4b and the clas- increases T cell alloreactivity against transplanted tissues (43, sical pathway convertase (28). Membrane cofactor protein 44). Furthermore, Ab-induced MAC on endothelial cells (CD46) and decay-accelerating factor (CD55) control activity enhances the response of alloreactive T cells and increases of the classical and alternative pathway convertases, and they their production of IFN-g (37). IFN-g, in turn, increases the are expressed on endothelial cells. Ab-mediated complement expression of HLA classes I and II by the endothelial cells, activation on endothelial cells may upregulate the expression leading to further Ab-mediated complement activation on the of membrane cofactor protein and CD59, increasing the re- cell surface. CR2 is expressed on B cells, and the ligation of sistance of the cells to complement-mediated injury (29). CR2 by C3d amplifies the response to target Ags (45). CR1 (CD35) is another membrane-bound regulator with Complement activation within the ischemic kidney was found both classical and alternative pathway regulatory activity. CR1 to amplify the humoral immune response to foreign Ags, The Journal of Immunology 5527 possibly via this mechanism (46). Thus, the complement biopsies”), only about half of the C4d+ patients developed system potentially influences AMR at many different steps. It AMR (52). As mentioned above, C4d deposition in ABO- may promote the development of DSA, it mediates the incompatible allografts can actually be associated with ac- downstream pathogenic effects of DSA, and it can increase the commodation and improved outcomes (53). Thus, detection expression of HLA on endothelial cells. of C4d without histologic or functional evidence of allograft Complement activation on endothelial cells is not always injury is not sufficient to predict AMR or to guide treatment. pathogenic, and it may be protective under some circum- The significance of C4d staining in lung and liver allografts is stances. Transient depletion of DSA in recipients of ABO- controversial (54–56). C3 and C4 are produced in the liver, incompatible allografts leads to long-term graft survival in and hepatocytes may be intrinsically resistant to complement- some patients. However, DSA titers rebound in these subjects mediated injury (57). and C4d can be detected within the allografts. This phe- The convertases deposit multiple C3b molecules on target nomenon is termed “accommodation,” and it may require surfaces, and the abundance of C3b can be many fold higher complement activation to occur (47). In a study of sensitized than that of C4b (58). C3d deposits can be seen in an identical primates, depletion of C3 with Yunnan-cobra venom factor pattern to C4d in some, but not all, allografts (51, 59). for 2 wk prior to kidney transplant prevented accelerated Cleavage of C3 occurs downstream of C4 in the classical AMR and resulted in prolonged graft survival (29). The an- pathway. Consequently, C3d is not seen in the absence of imals had persistent DSA and C3 levels returned to normal C4d in AMR (59, 60). Alternatively, the detection C4d in the after Yunnan-cobra venom factor was discontinued, yet none absence of C3d may represent effective complement regula- Downloaded from of the animals subsequently developed AMR. The acquired tion (Fig. 2B). Thus, C3d may be more specific than C4d as a resistance to complement-mediated injury may involve in- marker of complete complement activation and AMR (59), creased expression of complement regulatory proteins and although this requires further validation. upregulated mechanisms for removing sC5b-9 from the Although detection of C4d has long been considered es- plasma membrane (29, 48). sential for the diagnosis of AMR, there is emerging evidence

that DSA cause injury to allografts in the absence of C4d http://www.jimmunol.org/ C4d deposition within allografts deposits. Ultrastructural changes and endothelial-specific gene expression profiles characteristic of AMR are observed in some A unique feature of the complement system is that circulating 2 C3 and C4 proteins are cleaved and covalently fixed to nearby C4d biopsies (61, 62). Some reports now suggest that up to 20% of acute cases and up to 60% of cases of chronic AMR surfaces during activation, providing a durable marker of in- 2 flammation. The detection of C4d deposits in capillaries is a may be C4d (9, 63). The absence of C4d in these biopsies marker of acute and chronic AMR in transplanted kidneys (21, may be due to technical reasons, but DSA may also cause 49) and hearts (50) (Fig. 2A). C4d is a more sensitive indi- injury through complement-independent mechanisms, such cator of AMR than is IgG deposition, probably because it is as signaling through Fc receptors on NK cells or other cell by guest on September 27, 2021 types (64–66). Based on these observations, a category of more abundant and it is covalently fixed to the cell surface. 2 Isolated C4d deposition in kidney and heart allografts is not C4d AMR was included in the most recent revision of the Banff criteria for the diagnosis of AMR (9). Diagnosis of specific for AMR, however. In biopsies performed on patients 2 who did not have evidence of renal allograft injury (“protocol C4d AMR requires DSA, histologic evidence of injury, and detection of microvascular injury by or gene 2 expression profile. Patients with C4d AMR are at risk for long-term graft failure (62), and treatment of these patients improves outcomes, confirming the clinical importance this subgroup (67).

In vitro assays for donor-specific Abs The original CDC assay provides a functional readout of complement activation by DSA (i.e., lysis) (13). A positive crossmatch with this assay is highly predictive of acute rejection and is a contraindication to transplantation. The assay is not sensitive and is cumbersome to perform, however, and several other assays for DSA have subsequently been developed (the technical aspects of these assays have re- cently been reviewed in Ref. 68). In 1983, flow cytometric FIGURE 2. C4 and C3 deposition in tissues by the classical pathway of complement. (A and B) Linear staining of capillary for (A) crossmatching using recipient serum and donor lymphocytes FITC anti-C4d and (B) FITC anti-C3d in a cardiac from a patient was introduced as an alternative method (69), and flow with AMR. The staining pattern for C4d and C3d was identical in this bi- cytometry has largely replaced the CDC crossmatch. Addi- opsy. Original magnification 3400. (C) C3 and C4 deposition in glomerulus tionally, methods to detect DSA reactive to specific donor Ags of a mouse kidney. IgM deposition in the mesangium causes C4 deposition were developed in the mid-1990s (70). In these assays, recipient (red, detected with a Cy3 secondary Ab). Efficient complement regulation serum is mixed with beads coated with either HLA class I or prevents C3 deposition (green, FITC anti-C3) at the same location. Some alternative pathway–mediated C3 deposition is seen on Bowman’s capsule class II, and IgG bound to specific Ags is detected by flow and in the tubulointerstitium. Glomeruli are indicated with arrowheads. cytometry (71, 72). Modified with permission from Tan et al. (51) and Renner et al. (34). Hyperacute rejection has become rare since the adoption Original magnification 3400. of crossmatching using a combination of flow cytometry 5528 BRIEF REVIEWS: COMPLEMENT AND REJECTION crossmatch and the solid-phase single-Ag bead assay. Unfor- and atypical hemolytic uremic syndrome. The first case report tunately, these assays do not predict or detect AMR as well as of eculizumab used for AMR involved a highly sensitized originally hoped. Most studies agree that pretransplant DSA is kidney transplant recipient who developed severe AMR within associated with worse graft outcomes and a higher incidence of days of transplantation (92). The patient was resistant to acute and chronic AMR in kidney, heart, lung, liver, and standard Ab-depleting therapies but recovered renal function (73–77). In a study by Amico et al. after treatment with two doses of eculizumab. Additional (78), for example, pretransplant DSA was associated with an cases have been reported of successful treatment of acute increased incidence of AMR (55 versus 6%) and a reduced AMR in highly sensitized recipients of kidney (93, 94), 5-y death-censored graft survival compared with patients kidney/pancreas (95), heart (96), lung (97), and intestine (98) without detectable DSA. However, 45% of the patients with transplants. In the largest published trial to date, prophylac- detectable DSA did not develop AMR and did not have re- tic treatment of sensitized renal transplant patients with duced 5-y graft survival (78, 79). The poor specificity of the eculizumab in addition to plasmapheresis reduced the inci- standard DSA assays for predicting AMR may be due to the dence of acute AMR at 1 y compared with historical controls fact that they do not capture information about Ab isotype or (7.7 versus 42.2%), but it did not significantly reduce the in- its ability to activate complement. cidence of chronic AMR at 2 y (99, 100). Of patients with high DSA levels after transplant, positive C4d staining on biopsy DSA assays that measure complement binding/activation was common in both eculizumab-treated and control patients

To improve the ability of solid-phase assays to predict allograft (100 and 91%, respectively), consistent with the downstream Downloaded from injury, the single Ag bead assay has been modified to measure position of C5 in the complement cascade (Fig. 1B). In pa- complement activation by DSA against specific Ags. Assays tients with high DSA levels and positive C4d staining, how- have been developed that measure C1q or C3d binding by the ever, only 15% of patients in the treatment group had DSA, or that measure C4d deposition onto the bead surface inflammation consistent with AMR compared with 100% of (80–83). The C4d-deposition DSA assay correlates with C4d the historical controls. deposition in renal allografts (84), and it predicts worse al- Further analysis of the two patients in the eculizumab http://www.jimmunol.org/ lograft survival in cardiac (85) and renal transplants (86). In a treatment group that developed AMR revealed an association recent study of 1016 renal transplant patients, those with of IgM DSA with eculizumab failure (101). Burbach et al. C1q-binding DSA had worse graft survival than did those (102) reported two other cases of eculizumab failure, one in who did not: 18% of the patients developed T cell–mediated prevention of acute AMR and one in treatment of acute rejection and 48% of patients developed AMR (87). How- AMR. Both cases met Banff criteria for acute AMR but were 2 ever, detection of C1q-binding DSA has not correlated with C4d on biopsy. These cases may represent a subset of pa- AMR or allograft failure in all studies (88). Patients with tients who develop injury through complement-independent

C3d-binding DSA were found to have worse renal allograft mechanisms. It is also unknown how long treatment with by guest on September 27, 2021 survival than did those who do not, even in patients with low eculizumab should continue, and it is possible that prolonged overall DSA titers (81). The evaluation of C3d-binding DSA treatment will impede the development of accommodation. These was performed at the time of biopsy and was not evaluated are particularly important issues given the expense of the drug. over time, so the significance of these findings is limited to The early successes of eculizumab highlight the potential of acute AMR. complement-modulating therapies for preventing and treating A recent study reported that detection of IgG3 DSA in the AMR, whereas its failures underscore the heterogeneity of acute single-Ag bead assay is associated with a higher risk of allograft and chronic AMR. Clinical trials of eculizumab in transplant loss than other DSA isotypes (89). This is probably due to the patients are ongoing and should provide further insights into effects of isotype on the ability of Ig to activate complement. the optimal approach to complement inhibition in AMR Complement activation is also a function of DSA titer, (NCT01895127, NCT02113891, and NCT02013037). Several however, because bound IgG must achieve a certain degree of novel complement inhibitors are in development, some of which density to bind C1q. Indeed, positivity in the C1q-binding are being investigated as possible therapies for AMR (103). C1 assay is more strongly correlated with the overall level of DSA blockade prevented acute AMR of kidney allografts in allo- than it is with the isotype (90, 91). Thus, further studies are sensitized baboons (104), for example, and a recent phase I/II needed to determine whether the complement-binding assays trial of C1 inhibitor infusions showed promise in preventing yield clinically useful information beyond that provided by acute AMR in highly sensitized renal transplant patients (105). the standard single Ag bead assay and Ab titer, and whether Inhibition at the level of C3 may also be an effective approach the results of these assays will improve patient care. given the importance of C3 fragments in the innate and adaptive Complement-targeted therapies. Currently, the treatment of AMR immune responses (29). An agent that prevents C3 activation is based on strategies to remove preformed Abs (plasmaphe- within the transplanted organs is currently being evaluated in a resis) or to prevent production of new Abs (IVIg, , phase II study (106). bortezomib). Unfortunately, the treatment of acute and chronic AMR is often unsuccessful. Inhibition of the com- Conclusions plement cascade is an attractive therapeutic option, particularly AMR is an important cause of acute and chronic allograft in patients with acute disease and complement-activating DSA injury. Treatment is not always effective, and chronic AMR is detected by the solid-phase assays (81, 87). now the most common cause of long-term allograft failure. EculizumabisanmAbtoC5thatblocksC5cleavageand The degree of tissue injury caused by the humoral immune activation. The Food and Drug Administration has approved system is a function of the titer, affinity, and isotype of the eculizumab for treatment of paroxysmal nocturnal hemoglobinuria DSA, as well as the expression of Ags and complement regulatory The Journal of Immunology 5529 proteins within the target tissue. These elements are influ- 8. Cravedi, P., and P. S. Heeger. 2014. Complement as a multifaceted modulator of kidney transplant injury. J. Clin. Invest. 124: 2348–2354. enced by tissue injury, illness, and by immunosuppressive 9. Haas, M., B. Sis, L. C. Racusen, K. Solez, D. Glotz, R. B. Colvin, M. C. Castro, medications (or noncompliance). Consequently, the overall D. S. David, E. David-Neto, S. M. Bagnasco, et al. 2014. Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibody- tendency of DSA to cause injury varies over time, and the associated arterial lesions. Am. J. Transplant. 14: 272–283. diagnosis of AMR requires the detection of DSA in serum 10. Colvin, R. B. 2007. Antibody-mediated renal allograft rejection: diagnosis and and microvascular injury and/or C4d deposition within the pathogenesis. J. Am. Soc. Nephrol. 18: 1046–1056. 11. Zou, Y., P. Stastny, C. Susal,€ B. Do¨hler, and G. Opelz. 2007. against allograft. MICA and kidney-transplant rejection. N. Engl. J. Med. 357: 1293–1300. In recent years, there have been important advances in our 12. Jackson, A. M., T. K. Sigdel, M. Delville, S. C. Hsieh, H. Dai, S. Bagnasco, R. A. Montgomery, and M. M. Sarwal. 2015. Endothelial cell antibodies associ- understanding of the role of complement in AMR. One in- ated with novel targets and increased rejection. J. Am. Soc. Nephrol. 26: 1161– novation has been the development of assays to examine the 1171. 13. Patel, R., and P. I. Terasaki. 1969. Significance of the positive crossmatch test in complement-activating potential of DSA. These assays provide . N. Engl. J. Med. 280: 735–739. further evidence of the importance of the complement cascade 14. Gebel, H. M., R. S. Liwski, and R. A. Bray. 2013. Technical aspects of HLA in the pathogenesis of AMR. Eculizumab has shown efficacy antibody testing. Curr. Opin. Transplant. 18: 455–462. 15. Terasaki, P. I. 2003. Humoral theory of transplantation. Am. J. Transplant. 3: for the prevention and treatment of acute AMR, and new 665–673. therapeutic complement inhibitors are in development. Ad- 16. Halloran, P. F., J. Schlaut, K. Solez, and N. S. Srinivasa. 1992. The significance of the anti-class I response. II. Clinical and pathologic features of renal transplants ditional clinical experience with these drugs will provide im- with anti-class I-like antibody. Transplantation 53: 550–555. portant information about the benefits and limitations of 17. Trpkov, K., P. Campbell, F. Pazderka, S. Cockfield, K. Solez, and P. F. Halloran. 1996. Pathologic features of acute renal allograft rejection associated with donor- complement inhibition in this disease. For example, there may specific antibody: analysis using the Banff grading schema. Transplantation 61: Downloaded from be a subset of AMR patients in whom Ab-mediated injury of 1586–1592. the allograft does not involve complement activation. Fur- 18. Kobashigawa, J., M. G. Crespo-Leiro, S. M. Ensminger, H. Reichenspurner, A.Angelini,G.Berry,M.Burke,L.Czer,N.Hiemann,A.G.Kfoury,etal;Consensus thermore, C3a and/or C3b may contribute to allograft injury, Conference Participants. 2011. Report from a consensus conference on antibody- and complement inhibitors that block the complement cascade mediated rejection in . J. Heart Lung Transplant. 30: 252–269. 19. Wallace, W. D., S. S. Weigt, and C. F. Farver. 2014. Update on pathology of at the level of C3 may have advantages over agents that block antibody-mediated rejection in the lung allograft. Curr. Opin. Organ Transplant. the cascade at the level of C5. 19: 303–308. http://www.jimmunol.org/ One of the primary remaining challenges in caring for 20. Feucht, H. E., E. Felber, M. J. Gokel, G. Hillebrand, U. Nattermann, C. Brockmeyer, E. Held, G. Riethmuller,€ W. Land, and E. Albert. 1991. Vascular transplant recipients is detecting and monitoring AMR. An deposition of complement-split products in kidney allografts with cell-mediated ideal biomarker of AMR would specifically indicate active rejection. Clin. Exp. Immunol. 86: 464–470. 21. Feucht, H. E., H. Schneeberger, G. Hillebrand, K. Burkhardt, M. Weiss, complement activation and tissue injury, not just future risk of G. Riethmuller,€ W. Land, and E. Albert. 1993. Capillary deposition of C4d injury. Furthermore, biomarkers that indicate ongoing com- complement fragment and early renal graft loss. Kidney Int. 43: 1333–1338. 22. Racusen, L. C., R. B. Colvin, K. Solez, M. J. Mihatsch, P. F. Halloran, plement activation could be used to stratify patients to P. M. Campbell, M. J. Cecka, J. P. Cosyns, A. J. Demetris, M. C. Fishbein, et al. treatment with complement inhibitory drugs. Molecular im- 2003. Antibody-mediated rejection criteria—an addition to the Banff 97 classifi- cation of renal allograft rejection. Am. J. Transplant. 3: 708–714.

aging methods have been developed to noninvasively detect by guest on September 27, 2021 23. Colvin, M. M., J. L. Cook, P. Chang, G. Francis, D. T. Hsu, M. S. Kiernan, deposition of complement fragments within tissues (107), and J. A. Kobashigawa, J. Lindenfeld, S. C. Masri, D. Miller, et al; American Heart these techniques may be useful for monitoring AMR. These Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; American Heart Association Heart Failure and Transplanta- diagnostic tools and other future discoveries in the field of tion Committee of the Council on Cardiopulmonary Critical Care, Perioperative complement biology will undoubtedly have an important and Resuscitation; American Heart Association Heart Failure and Transplantation Committee of the Council on Cardiovascular Disease in the Young; American impact on prevention and treatment of AMR. Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing; American Heart Association Heart Failure and Transplantation Committee of the Council Disclosures on Cardiovascular Radiology and Intervention; American Heart Association Heart J.M.T. receives royalties from Alexion, Inc. and has received consulting fees Failure and Transplantation Committee of the Council on Cardiovascular Surgery from Baxter, Inc. The other authors have no financial conflicts of interest. and Anesthesia. 2015. Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. Circulation 131: 1608–1639. References 24. Duncan, A. R., and G. Winter. 1988. The binding site for C1q on IgG. Nature 332: 738–740. 1. Everly, M. J., J. J. Everly, L. J. Arend, P. Brailey, B. Susskind, A. Govil, A. Rike, 25. Bindon, C. I., G. Hale, M. Bruggemann,€ and H. Waldmann. 1988. Human P. Roy-Chaudhury, G. Mogilishetty, R. R. Alloway, et al. 2009. Reducing de novo monoclonal IgG isotypes differ in complement activating function at the level of donor-specific antibody levels during acute rejection diminishes renal allograft loss. C4 as well as C1q. J. Exp. Med. 168: 127–142. Am. J. Transplant. 9: 1063–1071. 26. Hughes-Jones, N. C., and B. Gardner. 1979. Reaction between the isolated 2. El Ters, M., J. P. Grande, M. T. Keddis, E. Rodrigo, B. Chopra, P. G. Dean, globular sub-units of the complement component C1q and IgG-complexes. Mol. M. D. Stegall, and F. G. Cosio. 2013. Kidney allograft survival after acute re- Immunol. 16: 697–701. jection, the value of follow-up biopsies. Am. J. Transplant. 13: 2334–2341. 27. Diebolder, C. A., F. J. Beurskens, R. N. de Jong, R. I. Koning, K. Strumane, 3. Nair, N., T. Ball, P. A. Uber, and M. R. Mehra. 2011. Current and future M. A. Lindorfer, M. Voorhorst, D. Ugurlar, S. Rosati, A. J. Heck, et al. 2014. challenges in therapy for antibody-mediated rejection. J. Heart Lung Transplant. Complement is activated by IgG hexamers assembled at the cell surface. Science 30: 612–617. 343: 1260–1263. 4. Einecke, G., B. Sis, J. Reeve, M. Mengel, P. M. Campbell, L. G. Hidalgo, 28. Blom, A. M., B. O. Villoutreix, and B. Dahlba¨ck. 2004. Complement inhibitor B. Kaplan, and P. F. Halloran. 2009. Antibody-mediated microcirculation injury C4b-binding protein-friend or foe in the ? Mol. Immunol. is the major cause of late kidney transplant failure. Am. J. Transplant. 9: 40: 1333–1346. 2520–2531. 29. Chen Song, S., S. Zhong, Y. Xiang, J. H. Li, H. Guo, W. Y. Wang, Y. L. Xiong, 5. Sellare´s, J., D. G. de Freitas, M. Mengel, B. Sis, L. G. Hidalgo, A. J. Matas, X. C. Li, S. Chen Shi, X. P. Chen, and G. Chen. 2011. Complement inhibition B. Kaplan, and P. F. Halloran. 2011. Inflammation lesions in kidney transplant enables renal allograft accommodation and long-term engraftment in presensitized biopsies: association with survival is due to the underlying diseases. Am. J. nonhuman primates. Am. J. Transplant. 11: 2057–2066. doi:10.1111/j.1600- Transplant. 11: 489–499. 6143.2011.03646.x 6. El-Zoghby, Z. M., M. D. Stegall, D. J. Lager, W. K. Kremers, H. Amer, 30. Collard, C. D., C. Bukusoglu, A. Agah, S. P. Colgan, W. R. Reenstra, J. M. Gloor, and F. G. Cosio. 2009. Identifying specific causes of kidney allograft B. P. Morgan, and G. L. Stahl. 1999. Hypoxia-induced expression of complement loss. Am. J. Transplant. 9: 527–535. receptor type 1 (CR1, CD35) in human vascular endothelial cells. Am. J. Physiol. 7. Everly, M. J., L. M. Rebellato, C. E. Haisch, M. Ozawa, K. Parker, K. P. Briley, 276: C450–C458. P. G. Catrou, P. Bolin, W. T. Kendrick, S. A. Kendrick, et al. 2013. Incidence and 31. Ollert, M. W., K. David, R. Bredehorst, and C. W. Vogel. 1995. Classical impact of de novo donor-specific alloantibody in primary renal allografts. Trans- complement pathway activation on nucleated cells. Role of factor H in the control plantation 95: 410–417. of deposited C3b. J. Immunol. 155: 4955–4962. 5530 BRIEF REVIEWS: COMPLEMENT AND REJECTION

32. Gershov, D., S. Kim, N. Brot, and K. B. Elkon. 2000. C-reactive protein binds to 55. Magro, C. M., A. Pope Harman, D. Klinger, C. Orosz, P. Adams, J. Waldman, apoptotic cells, protects the cells from assembly of the terminal complement D. Knight, M. Kelsey, and P. Ross, Jr. 2003. Use of C4d as a diagnostic adjunct in components, and sustains an antiinflammatory innate immune response: impli- lung allograft biopsies. Am. J. Transplant. 3: 1143–1154. cations for systemic . J. Exp. Med. 192: 1353–1364. 56. Neil, D. A., and S. G. Hubscher.€ 2010. Current views on rejection pathology in 33. Trouw, L. A., A. A. Bengtsson, K. A. Gelderman, B. Dahlba¨ck, G. Sturfelt, and . Transpl. Int. 23: 971–983. A. M. Blom. 2007. C4b-binding protein and factor H compensate for the loss of 57. Koch, C. A., A. Kanazawa, R. Nishitai, B. E. Knudsen, K. Ogata, T. B. Plummer, membrane-bound complement inhibitors to protect apoptotic cells against exces- K. Butters, and J. L. Platt. 2005. Intrinsic resistance of hepatocytes to complement- sive complement attack. J. Biol. Chem. 282: 28540–28548. mediated injury. J. Immunol. 174: 7302–7309. 34. Renner, B., D. Strassheim, C. R. Amura, L. Kulik, D. Ljubanovic, 58. Ollert, M. W., J. V. Kadlec, K. David, E. C. Petrella, R. Bredehorst, and M. J. Glogowska, K. Takahashi, M. C. Carroll, V. M. Holers, and J. M. Thurman. C. W. Vogel. 1994. Antibody-mediated complement activation on nucleated cells. 2010. B cell subsets contribute to renal injury and renal protection after ischemia/ A quantitative analysis of the individual reaction steps. J. Immunol. 153: 2213– reperfusion. J. Immunol. 185: 4393–4400. 2221. 35. Iwasaki, K., Y. Miwa, H. Ogawa, S. Yazaki, M. Iwamoto, T. Furusawa, A. Onishi, 59. Haas, M., M. H. Rahman, L. C. Racusen, E. S. Kraus, S. M. Bagnasco, T. Kuzuya, M. Haneda, Y. Watarai, et al. 2012. Comparative study on signal D. L. Segev, C. E. Simpkins, D. S. Warren, K. E. King, A. A. Zachary, and transduction in endothelial cells after anti-A/B and human leukocyte an- R. A. Montgomery. 2006. C4d and C3d staining in biopsies of ABO- and HLA- tibody reaction: implication of accommodation. Transplantation 93: 390–397. incompatible renal allografts: correlation with histologic findings. Am. J. Trans- 36. Cole, D. S., and B. P. Morgan. 2003. Beyond lysis: how complement influences plant. 6: 1829–1840. cell fate. Clin. Sci. 104: 455–466. 60. Rodriguez, E. R., D. V. Skojec, C. D. Tan, A. A. Zachary, E. K. Kasper, 37. Jane-Wit, D., T. D. Manes, T. Yi, L. Qin, P. Clark, N. C. Kirkiles-Smith, J. V. Conte, and W. M. Baldwin, III. 2005. Antibody-mediated rejection in P. Abrahimi, J. Devalliere, G. Moeckel, S. Kulkarni, et al. 2013. Alloantibody and human cardiac allografts: evaluation of immunoglobulins and complement complement promote T cell-mediated cardiac allograft vasculopathy through activation products C4d and C3d as markers. Am. J. Transplant. 5: 2778–2785. noncanonical nuclear factor-kB signaling in endothelial cells. Circulation 128: 61. Sis, B., and P. F. Halloran. 2010. Endothelial transcripts uncover a previously 2504–2516. unknown phenotype: C4d-negative antibody-mediated rejection. Curr. Opin. 38. Jane-wit, D., Y. V. Surovtseva, L. Qin, G. Li, R. Liu, P. Clark, T. D. Manes, Organ Transplant. 15: 42–48.

C. Wang, M. Kashgarian, N. C. Kirkiles-Smith, et al. 2015. Complement 62. Loupy, A., G. S. Hill, C. Suberbielle, D. Charron, D. Anglicheau, J. Zuber, Downloaded from membrane attack complexes activate noncanonical NF-kB by forming an Akt+ M. O. Timsit, J. P. Duong, P. Bruneval, D. Vernerey, et al. 2011. Significance of NIK+ signalosome on Rab5+ endosomes. Proc. Natl. Acad. Sci. USA 112: 9686– C4d Banff scores in early protocol biopsies of kidney transplant recipients with 9691. preformed donor-specific antibodies (DSA). Am. J. Transplant. 11: 56–65. 39. Klos, A., A. J. Tenner, K. O. Johswich, R. R. Ager, E. S. Reis, and J. Ko¨hl. 2009. 63. Sis, B., P. M. Campbell, T. Mueller, C. Hunter, S. M. Cockfield, J. Cruz, The role of the anaphylatoxins in health and disease. Mol. Immunol. 46: 2753– C. Meng, D. Wishart, K. Solez, and P. F. Halloran. 2007. Transplant glomer- 2766. ulopathy, late antibody-mediated rejection and the ABCD tetrad in kidney allo- 40. Platt, J. L., A. P. Dalmasso, B. J. Lindman, N. S. Ihrcke, and F. H. Bach. 1991. graft biopsies for cause. Am. J. Transplant. 7: 1743–1752.

The role of C5a and antibody in the release of heparan sulfate from endothelial 64. Zhang, X., and E. F. Reed. 2009. Effect of antibodies on endothelium. Am. J. http://www.jimmunol.org/ cells. Eur. J. Immunol. 21: 2887–2890. Transplant. 9: 2459–2465. 41. Laudes, I. J., J. C. Chu, M. Huber-Lang, R. F. Guo, N. C. Riedemann, 65. Lee, C. Y., S. Lotfi-Emran, M. Erdinc, K. Murata, E. Velidedeoglu, K. Fox- J. V. Sarma, F. Mahdi, H. S. Murphy, C. Speyer, K. T. Lu, et al. 2002. Expression Talbot, J. Liu, J. Garyu, W. M. Baldwin, III, and B. A. Wasowska. 2007. The and function of C5a receptor in mouse microvascular endothelial cells. J. Immunol. involvement of FcR mechanisms in antibody-mediated rejection. Transplantation 169: 5962–5970. 84: 1324–1334. 42. Yamakuchi, M., N. C. Kirkiles-Smith, M. Ferlito, S. J. Cameron, C. Bao, K. Fox- 66. Hirohashi, T., C. M. Chase, P. Della Pelle, D. Sebastian, A. Alessandrini, Talbot, B. A. Wasowska, W. M. Baldwin, III, J. S. Pober, and C. J. Lowenstein. J. C. Madsen, P. S. Russell, and R. B. Colvin. 2012. A novel pathway of chronic 2007. Antibody to triggers endothelial exocytosis. Proc. allograft rejection mediated by NK cells and alloantibody. Am. J. Transplant. 12: Natl. Acad. Sci. USA 104: 1301–1306. 313–321. 43. Vieyra, M., S. Leisman, H. Raedler, W. H. Kwan, M. Yang, M. G. Strainic, 67. Haas, M., and J. Mirocha. 2011. Early ultrastructural changes in renal allografts: M. E. Medof, and P. S. Heeger. 2011. Complement regulates CD4 T-cell help to correlation with antibody-mediated rejection and transplant glomerulopathy. Am. CD8 T cells required for murine allograft rejection. Am. J. Pathol. 179: 766–774. J. Transplant. 11: 2123–2131. by guest on September 27, 2021 44. Gueler, F., S. Rong, W. Gwinner, M. Mengel, V. Bro¨cker, S. Scho¨n, T. F. Greten, 68. Konvalinka, A., and K. Tinckam. 2015. Utility of HLA antibody testing in kidney H. Hawlisch, T. Polakowski, K. Schnatbaum, et al. 2008. Complement 5a re- transplantation. J. Am. Soc. Nephrol. 26: 1489–1502. ceptor inhibition improves renal allograft survival. J. Am. Soc. Nephrol. 19: 2302– 69. Horsburgh, T., S. Martin, and A. J. Robson. 2000. The application of flow 2312. cytometry to testing. Transpl. Immunol. 8: 3–15. 45. Dempsey, P. W., M. E. Allison, S. Akkaraju, C. C. Goodnow, and D. T. Fearon. 70. Pei, R., J. H. Lee, N. J. Shih, M. Chen, and P. I. Terasaki. 2003. Single human 1996. C3d of complement as a molecular adjuvant: bridging innate and acquired leukocyte antigen flow cytometry beads for accurate identification of human leu- immunity. Science 271: 348–350. kocyte antigen antibody specificities. Transplantation 75: 43–49. 46. Fuquay, R., B. Renner, L. Kulik, J. W. McCullough, C. Amura, D. Strassheim, 71. Sumitran-Karuppan, S., and E. Moller. 1996. The use of magnetic beads coated R. Pelanda, R. Torres, and J. M. Thurman. 2013. Renal ischemia-reperfusion with soluble HLA class I or class II proteins in antibody screening and for injury amplifies the humoral immune response. J. Am. Soc. Nephrol. 24: 1063– specificity determinations of donor-reactive antibodies. Transplantation 61: 1072. 1539–1545. 47. Park, W. D., J. P. Grande, D. Ninova, K. A. Nath, J. L. Platt, J. M. Gloor, and 72. Pei, R., G. Wang, C. Tarsitani, S. Rojo, T. Chen, S. Takemura, A. Liu, and J. Lee. M. D. Stegall. 2003. Accommodation in ABO-incompatible kidney allografts, a 1998. Simultaneous HLA class I and class II antibodies screening with flow novel mechanism of self-protection against antibody-mediated injury. Am. J. cytometry. Hum. Immunol. 59: 313–322. Transplant. 3: 952–960. 73. Otten, H. G., M. C. Verhaar, H. P. Borst, R. J. Hene´, and A. D. van Zuilen. 48. Shibata, T., F. G. Cosio, and D. J. Birmingham. 1991. Complement activation 2012. Pretransplant donor-specific HLA class-I and -II antibodies are associated induces the expression of decay-accelerating factor on human mesangial cells. J. with an increased risk for kidney graft failure. Am. J. Transplant. 12: 1618–1623. Immunol. 147: 3901–3908. 74. Dunn, T. B., H. Noreen, K. Gillingham, D. Maurer, O. G. Ozturk, T. L. Pruett, 49. Collins, A. B., E. E. Schneeberger, M. A. Pascual, S. L. Saidman, W. W. Williams, R. A. Bray, H. M. Gebel, and A. J. Matas. 2011. Revisiting traditional risk factors N. Tolkoff-Rubin, A. B. Cosimi, and R. B. Colvin. 1999. Complement activation for rejection and graft loss after kidney transplantation. Am. J. Transplant. 11: in acute humoral renal allograft rejection: diagnostic significance of C4d deposits 2132–2143. in peritubular capillaries. J. Am. Soc. Nephrol. 10: 2208–2214. 75. Amico, P., P. Hirt-Minkowski, G. Ho¨nger, L. Gurke,€ M. J. Mihatsch, J. Steiger, 50. Crespo-Leiro, M. G., A. Veiga-Barreiro, N. Dome´nech, M. J. Paniagua, P. Pin˜o´n, H. Hopfer, and S. Schaub. 2011. Risk stratification by the virtual crossmatch: a M. Gonza´lez-Cuesta, E. Va´zquez-Martul, C. Ramirez, J. J. Cuenca, and A. Castro- prospective study in 233 renal transplantations. Transpl. Int. 24: 560–569. Beiras. 2005. Humoral heart rejection (severe allograft dysfunction with no signs of 76. Lefaucheur, C., A. Loupy, G. S. Hill, J. Andrade, D. Nochy, C. Antoine, cellular rejection or ischemia): incidence, management, and the value of C4d for C. Gautreau, D. Charron, D. Glotz, and C. Suberbielle-Boissel. 2010. Preexisting diagnosis. Am. J. Transplant. 5: 2560–2564. donor-specific HLA antibodies predict outcome in kidney transplantation. J. Am. 51. Tan, C. D., G. G. Sokos, D. J. Pidwell, N. G. Smedira, G. V. Gonzalez-Stawinski, Soc. Nephrol. 21: 1398–1406. D. O. Taylor, R. C. Starling, and E. R. Rodriguez. 2009. Correlation of donor- 77. Tait, B. D., C. Susal,€ H. M. Gebel, P. W. Nickerson, A. A. Zachary, F. H. Claas, specific antibodies, complement and its regulators with graft dysfunction in cardiac E. F. Reed, R. A. Bray, P. Campbell, J. R. Chapman, et al. 2013. Consensus antibody-mediated rejection. Am. J. Transplant. 9: 2075–2084. guidelines on the testing and clinical management issues associated with HLA and 52. Sund, S., T. Hovig, A. V. Reisaeter, H. Scott, Ø. Bentdal, and T. E. Mollnes. non-HLA antibodies in transplantation. Transplantation 95: 19–47. 2003. Complement activation in early protocol kidney graft biopsies after living- 78. Amico, P., G. Ho¨nger, M. Mayr, J. Steiger, H. Hopfer, and S. Schaub. 2009. donor transplantation. Transplantation 75: 1204–1213. Clinical relevance of pretransplant donor-specific HLA antibodies detected by 53. Haas, M., D. L. Segev, L. C. Racusen, S. M. Bagnasco, J. E. Locke, D. S. Warren, single-antigen flow-beads. Transplantation 87: 1681–1688. C. E. Simpkins, D. Lepley, K. E. King, E. S. Kraus, and R. A. Montgomery. 2009. 79. Susal,€ C., J. Ovens, K. Mahmoud, B. Do¨hler, S. Scherer, A. Ruhenstroth, C4d deposition without rejection correlates with reduced early scarring in ABO- T. H. Tran, A. Heinold, and G. Opelz. 2011. No association of kidney graft loss incompatible renal allografts. J. Am. Soc. Nephrol. 20: 197–204. with human leukocyte antigen antibodies detected exclusively by sensitive Luminex 54. Glanville, A. R. 2010. Antibody-mediated rejection in : myth single-antigen testing: a Collaborative Transplant Study report. Transplantation or reality? J. Heart Lung Transplant. 29: 395–400. 91: 883–887. The Journal of Immunology 5531

80. Chen, G., F. Sequeira, and D. B. Tyan. 2011. Novel C1q assay reveals a clinically 2014. Eculizumab and splenectomy as salvage therapy for severe antibody- relevant subset of human leukocyte antigen antibodies independent of immuno- mediated rejection after HLA-incompatible kidney transplantation. Transplanta- globulin G strength on single antigen beads. Hum. Immunol. 72: 849–858. tion 98: 857–863. 81. Sicard, A., S. Ducreux, M. Rabeyrin, L. Couzi, B. McGregor, L. Badet, 95. Biglarnia, A. R., B. Nilsson, T. Nilsson, B. von Zur-Muhlen,€ M. Wagner, J. Y. Scoazec, T. Bachelet, S. Lepreux, J. Visentin, et al. 2015. Detection of C3d- C. Berne, A. Wanders, A. Magnusson, and G. Tufveson. 2011. Prompt reversal of binding donor-specific anti-HLA antibodies at diagnosis of humoral rejection a severe complement activation by eculizumab in a patient undergoing intentional predicts renal graft loss. J. Am. Soc. Nephrol. 26: 457–467. ABO-incompatible pancreas and kidney transplantation. Transpl. Int. 24: 82. Lachmann, N., K. Todorova, H. Schulze, and C. Scho¨nemann. 2013. Systematic e61–e66. comparison of four cell- and Luminex-based methods for assessment of 96. Irving, C. A., A. R. Gennery, V. Carter, J. P. Wallis, A. Hasan, M. Griselli, and complement-activating HLA antibodies. Transplantation 95: 694–700. R. Kirk. 2015. ABO-incompatible cardiac transplantation in pediatric patients ¨ ¨ 83. Wahrmann, M., M. Exner, B. Haidbauer, M. Schillinger, H. Regele, G. Kormoczi, with high isohemagglutinin titers. J. Heart Lung Transplant. 34: 1095–1102. ¨ and G. A. Bohmig. 2005. [C4d]FlowPRA screening—a specific assay for selective 97. Dawson, K. L., A. Parulekar, and H. Seethamraju. 2012. Treatment of hyperacute detection of complement-activating anti-HLA alloantibodies. Hum. Immunol. 66: antibody-mediated lung allograft rejection with eculizumab. J. Heart Lung 526–534. Transplant. 31: 1325–1326. 84. Bartel, G., M. Wahrmann, M. Exner, H. Regele, N. Huttary, M. Schillinger, 98. Fan, J., P. Tryphonopoulos, A. Tekin, S. Nishida, G. Selvaggi, A. Amador, G. F. Ko¨rmo¨czi, W. H. Ho¨rl, and G. A. Bo¨hmig. 2008. In vitro detection of C4d- fixing HLA alloantibodies: associations with capillary C4d deposition in kidney J. Jebrock, D. Weppler, D. Levi, R. Vianna, et al. 2015. Eculizumab salvage allografts. Am. J. Transplant. 8: 41–49. therapy for antibody-mediated rejection in a desensitization-resistant intestinal re- 85. Rose, M. L., and J. D. Smith. 2009. Clinical relevance of complement-fixing transplant patient. Am. J. Transplant. 15: 1995–2000. antibodies in cardiac transplantation. Hum. Immunol. 70: 605–609. 99. Stegall, M. D., T. Diwan, S. Raghavaiah, L. D. Cornell, J. Burns, P. G. Dean, 86. Wahrmann, M., G. Bartel, M. Exner, H. Regele, G. F. Ko¨rmo¨czi, G. F. Fischer, F. G. Cosio, M. J. Gandhi, W. Kremers, and J. M. Gloor. 2011. Terminal and G. A. Bo¨hmig. 2009. Clinical relevance of preformed C4d-fixing and non- complement inhibition decreases antibody-mediated rejection in sensitized renal C4d-fixing HLA single antigen reactivity in renal allograft recipients. Transpl. Int. transplant recipients. Am. J. Transplant. 11: 2405–2413. 22: 982–989. 100. Cornell, L. D., C. A. Schinstock, M. J. Gandhi, W. K. Kremers, and 87. Loupy, A., C. Lefaucheur, D. Vernerey, C. Prugger, J. P. Duong van Huyen, M. D. Stegall. 2015. Positive crossmatch kidney transplant recipients treated with N. Mooney, C. Suberbielle, V. Fre´meaux-Bacchi, A. Me´jean, F. Desgrandchamps, eculizumab: outcomes beyond 1 year. Am. J. Transplant. 15: 1293–1302. Downloaded from et al. 2013. Complement-binding anti-HLA antibodies and kidney-allograft sur- 101. Bentall, A., D. B. Tyan, F. Sequeira, M. J. Everly, M. J. Gandhi, L. D. Cornell, vival. N. Engl. J. Med. 369: 1215–1226. H. Li, N. A. Henderson, S. Raghavaiah, J. L. Winters, et al. 2014. Antibody- 88. Crespo, M., A. Torio, V. Mas, D. Redondo, M. J. Pe´rez-Sa´ez, M. Mir, A. Faura, mediated rejection despite inhibition of terminal complement. Transpl. Int. 27: R. Guerra, O. Montes-Ares, M. D. Checa, and J. Pascual. 2013. Clinical relevance 1235–1243. of pretransplant anti-HLA donor-specific antibodies: does C1q-fixation matter? 102. Burbach, M., C. Suberbielle, I. Broche´riou, C. Ridel, L. Mesnard, K. Dahan, Transpl. Immunol. 29: 28–33. E. Rondeau, and A. Hertig. 2014. Report of the inefficacy of eculizumab in two 89. Lefaucheur, C., D. Viglietti, C. Bentlejewski, J. P. Duong van Huyen, cases of severe antibody-mediated rejection of renal grafts. Transplantation 98:

D. Vernerey, O. Aubert, J. Verine, X. Jouven, C. Legendre, D. Glotz, et al. 2015. 1056–1059. http://www.jimmunol.org/ IgG donor-specific anti-human HLA antibody subclasses and kidney allograft 103. Ricklin, D., and J. D. Lambris. 2013. Progress and trends in complement thera- antibody-mediated injury. J. Am. Soc. Nephrol. DOI: 10.1681/ASN.2014111120. peutics. Adv. Exp. Med. Biol. 735: 1–22.doi:10.1007/978-1-4614-4118-2_1 90. Schaub, S., G. Ho¨nger, M. T. Koller, R. Liwski, and P. Amico. 2014. Determi- 104. Tillou, X., N. Poirier, S. Le Bas-Bernardet, J. Hervouet, D. Minault, K. Renaudin, nants of C1q binding in the single antigen bead assay. Transplantation 98: F. Vistoli, G. Karam, M. Daha, J. P. Soulillou, and G. Blancho. 2010. 387–393. Recombinant human C1-inhibitor prevents acute antibody-mediated rejection in 91. Yell, M., B. L. Muth, D. B. Kaufman, A. Djamali, and T. M. Ellis. 2015. C1q alloimmunized baboons. Kidney Int. 78: 152–159. binding activity of de novo donor-specific HLA antibodies in renal transplant 105. Vo, A. A., A. Zeevi, J. Choi, K. Cisneros, M. Toyoda, J. Kahwaji, A. Peng, recipients with and without antibody-mediated rejection. Transplantation 99: 1151–1155. R. Villicana, D. Puliyanda, N. Reinsmoen, et al. 2015. A phase I/II placebo- 92. Locke, J. E., C. M. Magro, A. L. Singer, D. L. Segev, M. Haas, A. T. Hillel, controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in K. E. King, E. Kraus, L. M. Lees, J. K. Melancon, et al. 2009. The use of antibody HLA sensitized patients. Transplantation 99: 299–308. 106. Pratt, J. R., M. E. Jones, J. Dong, W. Zhou, P. Chowdhury, R. A. Smith, and to complement protein C5 for salvage treatment of severe antibody-mediated re- by guest on September 27, 2021 jection. Am. J. Transplant. 9: 231–235. S. H. Sacks. 2003. Nontransgenic hyperexpression of a complement regulator in 93. Kocak, B., E. Arpali, E. Demiralp, B. Yelken, C. Karatas, S. Gorcin, N. Gorgulu, donor kidney modulates transplant ischemia/reperfusion damage, acute rejection, M. Uzunalan, A. Turkmen, and M. Kalayoglu. 2013. Eculizumab for salvage and chronic nephropathy. Am. J. Pathol. 163: 1457–1465. treatment of refractory antibody-mediated rejection in kidney transplant patients: 107. Serkova, N. J., B. Renner, B. A. Larsen, C. R. Stoldt, K. M. Hasebroock, case reports. Transplant. Proc. 45: 1022–1025. E. L. Bradshaw-Pierce, V. M. Holers, and J. M. Thurman. 2010. Renal inflam- 94. Orandi, B. J., A. A. Zachary, N. N. Dagher, S. M. Bagnasco, J. M. Garonzik- mation: targeted iron oxide nanoparticles for molecular MR imaging in mice. Wang, K. J. Van Arendonk, N. Gupta, B. E. Lonze, N. Alachkar, E. S. Kraus, et al. Radiology 255: 517–526.