Banz, Yara

Boesch, Claudia

Martinelli, Michele

Mohacsi, Paul

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The clinical relevance of antibody-mediated rejection: a new era ofheart transplantationPaul Mohacsia,*, Michele Martinellia, Yara Banzb and Claudia Boeschaa Department of Cardiology, Swiss Cardiovascular Center, University Hospital Bern (Inselspital), Bern, Switzerlandb Institute of Pathology, University of Bern, Bern, Switzerland* Corresponding author. Department of Cardiology, Swiss Cardiovascular Center, University Hospital Bern (Inselspital), Freiburgstrasse, CH 3010 Bern, Switzerland.Tel: +41-31-6324464; e-mail: paul.mohacsi@insel.ch (P. Mohacsi).Keywords: Heart transplantation • Antibody-mediated rejection • Antiendothelial-cell antibodies • Non-HLA antibodiesThis issue reports a case where the authors can be congratulatedon having saved the life of a patient who originally suffered fromgiant cell myocarditis and had been treated with cyclosporine(CyA), azathioprine (AZA) and corticosteroids (PDN) for 4 yearsbefore clinically deteriorating and been subjected to heart trans-plantation (HTx) [1]. The pretransplant work-up included humanleukocyte antigen (HLA)-typing of both patient and donor,screening for anti-HLA antibodies and cross-match with regardto T- and B-cells being negative. Postoperatively, conventionalimmunosuppression (CyA, AZA and PDN) was introduced. Therewere three HLA Class I and one HLA Class II allele mismatchesbetween donor and recipient.The ﬁrst endomyocardial biopsy (EMB) showed mild rejection(ISHLT 1R) without C4d deposition in immunohistochemistry. Thesecond EMB (3 weeks postoperatively) revealed severe macrophage(CD68+), and eosinophilic and lymphocytic inﬁltration, againwithout C4d deposition. The patient developed fever without clin-ical signs of infection and was treated under the presumption ofacute cellular rejection (ACR). After initial stabilization, the patientdeveloped cardiogenic shock 2 days later, which required urgenttreatment with extracorporeal membrane oxygenation, followed bythe implantation of a biventricular assist device the next day. Atthat time, EMB showed severe ACR (ISHLT 3R) and antibody-mediated rejection (AMR), strongly positive for C4d [2, 3]. The cyto-toxic T- and B-cell cross-match tests remained negative.The endothelial precursor cells cross-match test (EPC-XM;XM-ONE®, AbSorber AB, Sweden) was synchronously performedwith EMBs, measuring serum levels of the amount ofantiendothelial-cell antibodies (AECAs), either against donor-speciﬁc EPC’s or against autoreactive EPC’s (the patient’s ownEPCs). After initially being negative, donor-speciﬁc AECA becamepositive at the ﬁrst EMB (ISHLT 1R), but autoreactive AECAswere still negative. At the time of acute graft failure, the test wassurprisingly positive for both donor-speciﬁc and autoreactiveIgM antiendothelial AECA, but not for donor IgG AECA. Theauthors conclude that severe AMR was caused by non-HLA,AECAs. Epicrisis was successfully treated by plasmapheresis, in-travenous immunoglobulin (IVIgG), rituximab, muronomab-CD3,bortezomib and re-HTx. One month after re-HTx, the patient hadACR (ISHLT 2R), but remained free of AMR.During the last 15 years, AMR became a topic of major clinicalrelevance. Potential explanations are improved diagnostic tests andthe rising population of patients having undergone VAD implant-ation before HTx. Its pathophysiology remains unknown to date.AMR is often associated with haemodynamic compromise,increased mortality and development of graft coronary arterydisease (CAD). Younger age, congenital heart disease, positivedonor-speciﬁc cross-match, positive panel reactive antibody(PRA) titres, sensitization to OKT3, CMV seropositivity, previousblood transfusions and female gender have been identiﬁed asrisk factors for AMR [4].Ongoing discussions ﬁnally led to the consensus conferenceon April 20, 2010 in Chicago [5]. They also address the questionof non-HLA antibodies, such as vimentin, endothelial cells,MICA/MICB, with a very low incidence (2/128) by using thecurrent XM-One technique to separate EPCs from donor blood[6]. It was mentioned that ‘more work is required to understandwhether these assays can be used to diagnose AMR’.The association of AMR with cardiovascular mortality, such asdeath resulting from acute rejection, myocardial infarction, con-gestive heart failure, graft failure, arrhythmia or CAD, was recent-ly shown in paediatric HTx [7]. Such an observation supportsprotocol screening for AMR. However, the need for the treat-ment of measurable but clinically silent AMR and the algorithmto do so, still remains to be determined. Most of the transplantcentres continue to perform event-driven and individualizedstrategies, as shown in the current case report.Due to improved diagnostic testing and recently developedtherapeutic strategies, we do have the chance to avoid or totreat AMR individualized and sufﬁciently, either in the case ofpreformed (such as in ABO incompatibility) or acquired HLAantibodies (such as via pregnancy, prior transfusion or trans-plant). Some may argue that most of the measures against AMRneed intravenous administration, which is difﬁcult to maintainover the years. However, we can assume that ‘accommodation’will occur [8]. To provide an example of how to manage suchcases successfully, we would like to share the case of accidentalB to O incompatible HTx having been rescued successfullyby anti-B antibody absorption, plasma exchange with ABfresh frozen plasma, IVIgG, by using an anti-B antibody© The Author 2012. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.CASEREPORTSEuropean Journal of Cardio-Thoracic Surgery 42 (2012) 1047–1049 EDITORIAL COMMENTdoi:10.1093/ejcts/ezs536immunoadsorption column and the C1 esterase inhibitor(C1inh, Berinert®) [9]. The HTx patient survived 5 years anddeveloped a histo-blood group type change of the graft from Bto O [10].Another example is a desensitization protocol of acquiredanti-HLA Class I antibodies: a female patient underwent coronaryartery bypass grafting. Ten years later, the patient received agastric bypass due to adipositas permagna and colon resectiondue to diverticulitis. The patient had a previous pregnancy. Dueto intra-abdominal bleeding with haemorrhagic shock, splenec-tomy was required. Prolonged perioperative hypotension ledto an anterior myocardial infarction and congestive heart failure.As a consequence, left ventricular assist device (LVAD) implant-ation was required. Preoperative serum PRA levels were 43%,reaching postoperative serum PRA levels of 59%. In ﬂow cytome-try 10 days post-LVAD implantation, 21 different HLA Class Iantibodies were detected. The virtual cross-match (etrl.eurotransplant.org/cms/index.php?page=services) yielded a verylow likelihood for receiving a matching cardiac allograft. As de-sensitization protocol, we administered mycophenolic mofetil,rituximab and repetitive Protein-A immunoadsorption. Aftersingle rituximab administration, the absolute B-cell countdropped to <25/µl. Figure 1 depicts the desensitization protocolwith a consecutive decrease of the PRA levels. The patient ﬁnallyunderwent HTx with two unfavourable matches (HLA-B8 andB27); we continued during the postoperative phase withProtein-A immunoadsorption procedures. The EMB 1 week afterHTx showed slightly swollen endothelial cells, which led to theadministration of IvIgG and C1inh. Figure 2 shows immunohisto-chemical staining of the heart biopsies. The EMB 2 weeks afterHTx showed ACR (International Society of Heart and LungTransplantation 2R), which was treated with methylprednisoloneFigure 2: Immunohistochemical staining of heart biopsies: positive staining ishighlighted by a brown colour. Detection of the classical complementpathway component C4d and terminal membrane attack complex C5b-9 aswell as tissue macrophages by CD68.Figure 1: Desensitization protocol of the patient.V. Sigurdardottir et al. / European Journal of Cardio-Thoracic Surgery1048and rATG-Fresenius. Six years after HTx, the patient continues tobe ﬁne.The current case report by Sigurdardottir et al. and our exam-ples show that AMR is a contemporary clinical challenge, whichcan be reasonable diagnosed, addressed and solved in an appro-priate fashion.One week after HTx (left panel) only minimal complement de-position was observed in small capillaries and larger vessels. Thisis an unspeciﬁc feature and may be observed in the immediateperitransplant period, e.g. following graft ischaemia/reperfusion.CD68 marks some scattered macrophages. Endothelial cells areﬂat and general cellularity is low. A minimal perivascularlymphocyte-predominant inﬁltrate suggests minor ACR.Three weeks after transplantation (right panel), there is stillonly minimal C4d deposition, and slightly more C5b-9, however,mainly localized to larger blood vessels. Macrophage countsremain constant. The endothelial lining of only a few capillariesappears slightly swollen, accompanied by a perivascular andinterstitial lymphocyte-predominant inﬁltrate, suggesting ACR(top right panel). Hallmark features of AMR, including a moregeneralized swelling of the endothelial lining, thrombi in smallvessels, oedema and haemorrhage as well as intravascular accu-mulation of macrophages, were not noted.ACKNOWLEDGEMENTSThis work was supported by the Katharina Huber-SteinerFoundation.REFERENCES[1] Sigurdardottir V, Kolsrud O, Hernandez N, Dellgren G. Endothelial cellantibody-mediated rejection and successful retransplantation in a hearttransplanted patient. Eur J Cardiothorac Surg 2012;42:1044–6.[2] Reed EF, Demetris AJ, Hammond E, Itescu S, Kobashigawa JA,Reinsmoen NL et al. Acute antibody-mediated rejection of cardiac trans-plants. J Heart Lung Transplant 2006;25:153–9.[3] Berry GJ, Angelini A, Burke MM, Bruneval P, Fishbein MC, Hammond Eet al. The ISHLT working formulation for pathologic diagnosis ofantibody-mediated rejection in heart transplantation: evolution andcurrent status (2005–2011). J Heart Lung Transplant 2011;30:601–11.[4] Uber WE, Self SE, Van Bakel AB, Pereira NL. Acute antibody mediated re-jection following heart transplantation. Am J Transplant 2007;7:2064–74.[5] Kobashigawa J, Crespo-Leiro MG, Ensminger SM, Reichenspurner H,Angelini A, Berry G et al. Report from a consensus conference onantibody-mediated rejection in heart transplantation. J Heart LungTransplant 2011;30:252–69.[6] Nowak G, Karrar A, Holmén C, Nava S, Uzunel M, Hultenby K et al.Expression of vascular endothelial growth factor receptor-2 or Tie-2 onperipheral blood cells deﬁnes functionally competent cell populationscapable of reendothelialization. Circulation 2004;110:3699–707.[7] Everitt MD, Hammond MEH, Snow GL, Stehlik J, Revelo MP, Miller DVet al. Biopsy-diagnosed antibody-mediated rejection based on the pro-posed ISHLT working formulation is associated with adverse cardiovas-cular outcomes after pediatric heart transplant. J Heart Lung Transplant2012;31:686–93.[8] Soares MP, Lin Y, Sato K, Stuhlmeier KM, Bach FH. Accomodation.Immunol Today 1999;20:434–7.[9] Mohacsi P, Rieben R, Sigurdsson G, Tschanz H, Schaffner T, Nydegger UEet al. Successful management of a B-type cardiac allograft into an 0-typeman with 3 1/2 year clinical follow-up. Transplantation 2001;72:1328–30.[10] Koestner SC, Kappeler A, Schaffner T, Carrel TP, Nydegger UE, MohacsiP. Histo-blood group type change of the graft from B to O after ABOmismatched heart transplantation. Lancet 2004;363:1523–5.CASEREPORTSV. Sigurdardottir et al. / European Journal of Cardio-Thoracic Surgery 1049

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