Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside (original) (raw)
Related papers
Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation
American Journal of Transplantation, 2020
Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) directed against mismatched donor HLA is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non-HLA antibodies has become more prominent as AMR can be diagnosed in the absence of circulating DSA. Here, we assessed a single-center cohort of 64 orthotopic heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients with ≥pAMR1 (n=43) and non-AMR (n=21) were tested for reactivity against a panel of 44 non-HLA autoantigens. The AMR group had a significantly greater percentage of patients with elevated reactivity to autoantigens compared to non-AMR (p=0.002) and healthy controls (n=94, p<0.0001). DSA-positive AMR patients exhibited greater reactivity to autoantigens compared to DSA-negative (p<0.0001) and AMR patients with DSA and PRA>10% were identified as the subgroup with significantly elevated responses. Four antigens, vimentin, tubulin alpha 1B, lamin A/C and apolipoprotein L2, were significantly different between AMR and non-AMR. Moreover, increased reactivity to these antigens was associated with graft failure. These results suggest that antibodies to non-HLA are associated with DSA-positive AMR although their specific role in mediating allograft injury is not yet understood.
Outcome-Based Risk Assessment of Non-HLA Antibodies in Heart Transplantation: A Systematic Review
The Journal of Heart and Lung Transplantation, 2024
Background: Current monitoring after heart transplantation (HT) employs repeated invasive endomyocardial biopsies (EMB). Although positive EMB confirms rejection, EMB fails to predict impending, sub-clinical, or EMB-negative rejection events. While non-HLA antibodies have emerged as important risk factors for antibody-mediated rejection (AMR) after HT, their use in clinical risk stratification has been limited. A systematic review of the role of non-HLA antibodies in rejection pathologies has potential to guide efforts to overcome deficiencies of EMB in rejection monitoring. Methods: Databases were searched to include studies on non-HLA antibodies in HT recipients. Data collected included: number of patients, type of rejection, non-HLA antigen studied, association of non-HLA antibodies with rejection, and evidence for synergistic interaction between non-HLA antibodies and HLA-DSA responses. Results: A total of 56 studies met the inclusion criteria. Strength of evidence for each non-HLA antibody was evaluated based on the number of articles and patients in support vs. against their role in mediating rejection. Importantly, despite previous intense focus on the role of anti-MHC class I chain-related gene A (MICA) and anti-angiotensin II type I receptor (AT1R) antibodies in HT rejection, evidence for their involvement was equivocal. Conversely, strength of evidence for other non-HLA antibodies supports that differing rejection pathologies are driven by differing non-HLA antibodies. Conclusion: This systematic review underscores the importance of identifying peri-HT non-HLA antibodies. Current evidence supports the role of non-HLA antibodies in all forms of HT rejection. Further investigations are required to define the mechanisms of action of non-HLA antibodies in HT rejection.
The Journal of Heart and Lung Transplantation, 2017
Introduction-Donor specific anti-HLA antibodies (DSA) are common following heart transplantation and are associated with rejection, cardiac allograft vasculopathy (CAV), and mortality. Currently a non-invasive diagnostic test for pathologic AMR (pAMR) does not exist. Methods-221 consecutive adult patients underwent heart transplantation from January 1 st , 2010 through August 31 th , 2013 and followed through October 1 st , 2015. The primary objective was to determine whether the presence of DSA could detect AMR at the time of pathologic diagnosis. Secondary analyses included the association of DSA (stratified by MHC Class and de-novo status) during AMR with new graft dysfunction, graft loss (mortality or retransplantation), and development of CAV. Results-During the study period 69 individual patients (31.2%) had DSA (24% had de-novo DSA) and there were 74 episodes of pAMR in 38 unique patients. The sensitivity of DSA at any MFI to detect concurrent pAMR was only 54.3%. The presence of any DSA during pAMR increased the odds of graft dysfunction (OR 5.37, 95% CI 1.34-21.47, p=0.018), adjusting for age, gender, and timing of AMR. Circulating Class II DSA after transplantation increased the risk of future pAMR (HR 2.97, 95% CI 1.31-6.73, p=0.009). Patients who developed de-novo Class II DSA had a 151% increase in risk of graft loss (contingent on 30-day survival) compared with those who did not have DSA (95% CI 1.11-5.69, p=0.027).
Anti-HLA antibodies in heart transplantation
Transplant Immunology, 2004
We have analyzed the relationship between the development of transplant-related coronary artery disease (TRCAD) and the following potential risk factors: (a) number of HLA mismatches between recipient and donor; (b) production of anti-HLA antibodies; (c) growth of lymphocytes infiltrating the graft; and (d) frequency of biopsy proven episodes of acute rejection. The study population consisted of 285 adult heart allograft
Donor–specific HLA-DQ antibodies may contribute to poor graft outcome after heart transplantation
Annals of Saudi Medicine, 2018
BACKGROUND: HLA-DQ donor-specific antibodies (DSA) are implicated in allograft dysfunction after renal and lung transplantation. Limited data exists on the impact of HLA-DQ antibodies on heart transplant patients. OBJECTIVE: To investigate the impact of DSA formation on allograft function and outcomes in heart transplant patients. DESIGN: Retrospective cohort study. SETTING: Collating post-transplantation patient data from computerized database in a tertiary hospital in Riyadh, Saudi Arabia from January 2006 to October 2014. PATIENTS AND METHODS: We excluded recipients with positive preoperative complement-dependent-cytotoxicity crossmatch grafts and those with preformed DSA. Anti-HLA antibodies were identified using Luminex-based assay in sera collected before transplantation with a routine endomyocardial biopsy the first year and then annually. MAIN OUTCOME MEASURES: Primary outcome measures were allcause mortality, development of antibody mediated rejection, treated acute cellular rejection (ACR) and cardiac allograft vasculopathy (CAV). SAMPLE SIZE: 127 patients. RESULTS: DSA formation occurred in 43/127 (34%), with 33/43 (77%) targeting HLA-DQ antigens alone (n=7) or in combination with-DR,-A or B antibodies (n=26). Most (76%) were male and the mean (SD) age was 36 (14) years. Ten patients developed-A,-B or-DR antibodies without-DQ antibodies also present. Treated ACR (P=.011), reduced left ventricular ejection fraction (P<.001), CAV development (P=.003), and all-cause mortality (P=.01) were all significantly more prevalent in the DSA-positive cohort. CONCLUSION: HLA-DQ donor-specific antibodies were the most common type detected and may play a significant role in poor outcomes post-cardiac transplantation. This emphasizes the importance of HLA-DQ matching and monitoring for DSA formation in order to minimize post-transplantation immunological risk. LIMITATIONS: Retrospective design comes with inherent biases, results from single institute, with a particularly young cohort.
FLOW CYTOMETRIC DETECTION OF HLA-SPECIFIC ANTIBODIES AS A PREDICTOR OF HEART ALLOGRAFT REJECTION1
Transplantation, 2000
Background. Historically, panel reactive antibody (PRA) analysis to detect HLA antibodies has been performed using cell-based complement-dependent cytotoxicity (CDC) techniques. Recently, a flow cytometric procedure (FlowPRA) was introduced as an alternative approach to detect HLA antibodies. The flow methodology, using a solid phase matrix to which soluble HLA class I or class II antigens are attached is significantly more sensitive than CDC assays. However, the clinical relevance of antibodies detected exclusively by FlowPRAhas not been established. In this study of cardiac allograft recipients, FlowPRA was performed on pretransplant sera with no detectable PRA activity as assessed by CDC assays. FlowPRA antibody activity was then correlated with clinical outcome.
The Annals of Thoracic Surgery, 1990
Prospective human lymphocyte antigen (HLA) typing is not performed for heart transplantation, and the relation between HLA matching and cardiac graft rejection is unclear. Recipient and donor HLA matching were analyzed retrospectively in 51 patients undergoing orthotopic cardiac transplantation. Immunosuppression was based on cyclosporine and prednisone. During the mean follow-up of 34 months (range, 16 to 63 months), the 46 operative survivors had an average of 3.95 rejection episodes (range, zero to 11 episodes). Twenty-one patients had steroid-resistant rejection requiring treatment with polyclonal or monoclonal antithymocyte globulin. Human lymphocyte antigen typing was available for 44 patients, and antigens were grouped in broad specificities. Patients with two or more HLA-A or HLA-B matches ince the introduction of cyclosporine, cardiac trans-S plantation has become an accepted therapy for endstage cardiac dysfunction. Cardiac transplant recipient survival during the first year after transplantation approaches 90% [l-31. However, rejection remains a major cause of morbidity and death. Rejection has been implicated as the cause of death in 30% to 50% of late deaths [4-61. In other fields of organ transplantation, attention has focused on the impact of the human lymphocyte antigen (HLA) system on graft survival and rejection. A number of large multicenter studies have demonstrated For editorial comment see page 177.
Pediatric transplantation, 2011
There is increasing evidence that DSA are associated with poor graft survival, although there are little data in children. We aimed to describe the incidence of DSA in this group and to determine correlation with graft survival. HLA antibodies were analysed in 59 paediatric cardiac transplant recipients. Mean age 10.4 (0.7-18.5) yr, mean time post-transplant 5.1 (0.3-17.3) yr. Antibody detection/identification was performed on the Luminex platform with subsequent identification using Lifescreen Identification kits/One-Lambda Single antigen kits. Forty patients (69%) had no HLA antibodies. DSA were found in four (7%). One had transient Class I antibodies and normal cardiac function. The other three had persistent Class II antibodies (two subsequently required re-transplantation, the third had cardiac failure due to CAV). Non-DSA were found in 15 (25%), all with normal graft function and without rejection. There was no difference in function or CAV prevalence between those with non-DS...