The Role of Donor-Specific Antibodies in Acute Cardiac Allograft Dysfunction in the Absence of Cellular Rejection

Background Acute allograft dysfunction (AAD) is an important cause of morbidity among heart transplant recipients. The role of donor-specific antibodies (DSAs) in AAD, with the increasing use of single antigen bead (SAB) assays that have improved the ability to detect DSA, remains unclear. Methods We retrospectively reviewed 329 heart transplant recipients followed up at our institution. AAD was defined as an acute decline in left ventricular ejection fraction to less than 50% and a decrement of 10% or higher compared to baseline in the absence of cellular rejection. Patients with AAD were compared with matched 30 heart transplant controls. Results There were 10 (3%) patients with AAD, 4 (40%) had DSA detectable by SAB assay compared to 16 (53%) controls (P=0.43). Peak DSA mean fluorescent intensity (MFI) levels were significantly higher at baseline (class I and class II) in AAD compared to controls. DSA MFI values increased at the time of AAD and returned to baseline values during follow-up for these patients with AAD (P<0.05) but remained unchanged over time for controls. Six (60%) patients with AAD and 1 (3%) control had antibody-mediated rejection (AMR) by endomyocardial biopsy (P<0.01). There were 4 (40%) patients with AAD with no DSA or AMR. Conclusions AAD after heart transplant is a heterogeneous process characterized by 1) AMR and DSA, 2) AMR but no DSA, and 3) no AMR or DSA. The presence of DSA is not associated with AAD, but the quantity assessed by MFI levels may play a role.

[1]  William C Chapman,et al.  Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection. , 2013, Human immunology.

[2]  J. Wald,et al.  Correlation of circulating donor-specific anti-HLA antibodies and presence of C4d in endomyocardial biopsy with heart allograft outcomes: a single-center, retrospective study. , 2013, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[3]  R. Rodeheffer,et al.  Donor-Specific Antibodies to Class II Antigens Are Associated With Accelerated Cardiac Allograft Vasculopathy: A Three-Dimensional Volumetric Intravascular Ultrasound Study , 2013, Transplantation.

[4]  J. Lunz,et al.  Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients. , 2013, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[5]  W. Kremers,et al.  Effect of pretransplant human leukocyte antigen antibodies detected by solid-phase assay on heart transplant outcomes. , 2011, Transplantation proceedings.

[6]  A. Angelini,et al.  Report from a consensus conference on antibody-mediated rejection in heart transplantation. , 2011, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[7]  A. Sinha,et al.  New-onset graft dysfunction after heart transplantation--incidence and mechanism-related outcomes. , 2011, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[8]  R. Starling,et al.  International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. , 2010, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[9]  N. Smedira,et al.  Correlation of Donor‐Specific Antibodies, Complement and Its Regulators with Graft Dysfunction in Cardiac Antibody‐Mediated Rejection , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[10]  M. Fishbein,et al.  Asymptomatic antibody-mediated rejection after heart transplantation predicts poor outcomes. , 2009, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[11]  E. Reed,et al.  Report from a consensus conference on the sensitized patient awaiting heart transplantation. , 2009, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[12]  W. Kremers,et al.  Cardiac Allograft Remodeling After Heart Transplantation Is Associated with Increased Graft Vasculopathy and Mortality , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  S. Webber,et al.  Characterization of C4d Immunostaining Utilizing Paraffin-Embedded Tissue of Nonpresensitized Pediatric Heart Transplant Patients , 2008, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[14]  W. S. Ring,et al.  Antibodies Against Donor Human Leukocyte Antigens and the Outcome of Cardiac Allografts in Adults and Children , 2007, Transplantation.

[15]  N. Pereira,et al.  Acute Antibody‐Mediated Rejection Following Heart Transplantation , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  M. Fishbein,et al.  Acute antibody-mediated rejection of cardiac transplants. , 2006, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[17]  Richard B Devereux,et al.  Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardio , 2005, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[18]  Silviu Itescu,et al.  Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. , 2005, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[19]  M. Stegall,et al.  Persistence of Low Levels of Alloantibody after Desensitization in Crossmatch-Positive Living-Donor Kidney Transplantation , 2004, Transplantation.

[20]  M. Rose De novo production of antibodies after heart or lung transplantation should be regarded as an early warning system. , 2004, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[21]  M. Fishbein,et al.  Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. , 2003, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[22]  S. Takemoto,et al.  Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection. , 2000, Transplantation.

[23]  B. Meiser,et al.  Detection of humoral rejection in human cardiac allografts by assessing the capillary deposition of complement fragment C4d in endomyocardial biopsies. , 1999, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[24]  D. Freimark,et al.  The clinical significance of antibodies to human vascular endothelial cells after cardiac transplantation. , 1999, Transplantation.

[25]  Scott A. Chapman,et al.  Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database. , 1997, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[26]  M. Fishbein,et al.  Clinical-pathologic features of humoral rejection in cardiac allografts: a study in 81 consecutive patients. , 1995, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[27]  G Opelz,et al.  The influence of HLA compatibility on graft survival after heart transplantation. The Collaborative Transplant Study. , 1994, The New England journal of medicine.

[28]  E. Hammond,et al.  Vascular rejection and its relationship to allograft coronary artery disease. , 1992, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[29]  R. Nakhleh,et al.  Correlation of endomyocardial biopsy findings with autopsy findings in human cardiac allografts. , 1992, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[30]  C. Marboe,et al.  The role of anti-HLA antibodies in heart transplantation. , 1991, Transplantation.

[31]  C. Mock,et al.  Changes in left ventricular systolic function that accompany rejection of the transplanted heart: a serial radionuclide assessment of fifty-three consecutive cases. , 1991, American heart journal.

[32]  D. Renlund,et al.  Vascular (humoral) rejection in heart transplantation: pathologic observations and clinical implications. , 1989, The Journal of heart transplantation.

[33]  E. Stinson,et al.  Serial transvenous biopsy of the transplanted human heart. Improved management of acute rejection episodes. , 1974, Lancet.

[34]  D. Harrison,et al.  Acute Rejection in the Long‐Term Cardiac Transplant Survivor: Clinical Diagnosis, Treatment and Significance , 1974, Circulation.