Cardiac Antibody-mediated Rejection Research Articles

Clinical Utility of Donor-Derived Cell-Free DNA in Heart Transplant Recipients With Multi-Organ Transplants.

Donor-derived cell-free DNA (dd-cfDNA) has emerged as a reliable, noninvasive method for the surveillance of allograft rejection in heart transplantation (HT) patients, but its utility in multi-organ transplants (MOT) is unknown. We describe our experience using dd-cfDNA in simultaneous MOT recipients. A single-center retrospective review of all HT recipients between 2018 and 2022 that had at least one measurement of dd-cfDNA collected.Patients who had simultaneous MOT were identified and included in this study.Levels of dd-cfDNA were paired with endomyocardial biopsies (EMB) performed within 1 month of blood testing if available. Acute cellular rejection (ACR) was defined as ISHLT (International Society for Heart and Lung Transplantation) grade≥2R. and antibody-mediated rejection (AMR) was defined as pAMR grade > 0.The within-patient variability score of the dd-cfDNA was calculated by the variance/average. The study included 25 multiorgan transplant recipients: 13 heart-kidney (H-K), 8 heart-liver (H-Li), and 4 heart-lung (H-Lu). The median age was 55 years, 44% were female; the median time from HT until the first dd-cfDNA measurement was 4.5 months (IQR 2, 10.5).The median dd-cfDNA level was 0.18% (IQR 0.15%, 0.27%) for H-K, 1.15% (IQR 0.77%, 2.33%) for H-Li, and 0.69% (IQR 0.62%, 1.07%) for H-Lu patients (p < 0.001).Prevalence of positive dd-cfDNA tests (threshold of 0.20%) were 42.2%, 97.3%, and 92.3% in the H-K, H-Li, and H-Lu groups, respectively. The within-patient variability score was highest in the H-Li group (median of 0.45 [IQR 0.29, 0.94]) and lowest in the H-K group (median of 0.09 [IQR 0.06, 0.12]); p = 0.002. No evidence of cardiac ACR or AMR was found. Three patients experienced renal allograft ACR and/or AMR, two patients experienced rejection of the liver allograft, and one patient experienced an episode of AMR-mediated lung rejection. One person in the H-K group experienced an episode of cardiac allograft dysfunction that was not associated with biopsy-confirmed rejection. Dd-cfDNA is chronically elevated in most MOT recipients.There is a high degree of within-patient variability in levels (particularly for H-Li and H-Lu recipients), which may limit the utility of this assay in monitoring MOT recipients.

Feasibility of Interleukin-6 Receptor Blockade in Cardiac Antibody-mediated Rejection.

Antibody-mediated rejection (AMR) remains a significant cause of heart transplant mortality with few effective therapies. This study aimed to describe initial experience of using interleukin-6 receptor blockade with tocilizumab in the treatment of acute cardiac AMR at Barnes-Jewish Hospital/Washington University Transplant Center from July 2017 to May 2021 (n = 7). Clinical, echocardiographic, and serum alloantibody data were analyzed before and after treatment. All participants demonstrated marked improvement in functional status. Echocardiographic data following 4-6 mo of tocilizumab revealed significant improvements in biventricular systolic function for all participants. Consistent reductions in donor-specific HLA or angiotensin type I receptor antibodies were not observed, suggesting that tocilizumab may act downstream of antibody production. No patient experienced drug-related complications that necessitated discontinuation of therapy. These findings provide initial insights into the safety and efficacy of interleukin-6 receptor blockade in the treatment of cardiac AMR and support the design of larger prospective studies.

Abstract 14413: Possible Antibody Mediated Cardiac Rejection After Combined Heart-Kidney Transplant in a Sensitized Patient Associated to COVID-19 Pneumonia

Background: Antibody mediated rejection (AMR) starts with the appearance of donor-specific antibodies (DSA), followed by graft injury that may be subclinical and can progress to cardiac allograft vasculopathy (CAV) and chronic graft dysfunction. Case report A 48-year-old man with a past medical history of right nephrectomy due to congenital renal atrophy and dilated cardiomyopathy required heart transplantation at age 31, presented an episode of AMR grade 2 ten years post-transplant developing CAV with graft loss and end-stage renal disease. He was listed for a combined heart-kidney transplant. His panel reactive antibody (PRA) level was 40%, requiring desensitization therapy (plasmapheresis, intravenous gamma globulin and rituximab). At age 44, he received a heart-kidney transplant. Methylprednisolone and rabbit antithymocyte globulin were used for induction and desensitization therapy with plasmapheresis and intravenous gamma globulin at months 0-3-6-12 was continued. Maintenance immunosuppression therapy continued with tacrolimus, mycophenolic acid and prednisone. During follow-up persistent circulating DSA anti-class II HLA were detected and PRA reached 80%. He was admitted with a multifocal COVID-19 pneumonia. He had received 4 doses of the messenger RNA vaccine BNT162b2. Dexamethasone was started and mycophenolic acid was discontinued for 14 days. He did not need mechanical ventilation. Echocardiogram revealed marked concentric LVH, LVEF = 60%, grade II diastolic dysfunction and reduced global longitudinal strain (-7,6%). Pro-BNP was 962 pg/ml, and Troponin T 100 pg/ml. Endomyocardial biopsy showed no signs of cellular rejection nor capillary injury. Immunopathologic findings were negative. Coronary angiogram showed no significant lesions. AMR was suspected, the patient was treated with methylprednisolone, plasmapheresis and intravenous gamma globulin. Clinical response was satisfactory, and he was discharged in functional class I (NYHA). Conclusions Although both histological and immunopathologic studies were negative, clinical suspicion for AMR in a highly sensitized patient prevailed in the context of a recent infectious intercurrence. Other diagnosis cannot be completely ruled out in this clinical scenario.

Late Cardiac Antibody-Mediated Rejection: A Only Heart Duel.

Late Cardiac Antibody-Mediated Rejection: A Only Heart Duel.

Microvascular Inflammation: An Incremental Path to Refining the Diagnosis of Antibody-mediated Rejection in Heart Transplantation

Microvascular Inflammation: An Incremental Path to Refining the Diagnosis of Antibody-mediated Rejection in Heart Transplantation

Correlation Between Microvascular Inflammation in Endomyocardial Biopsies and Rejection Transcripts, Donor-specific Antibodies, and Graft Dysfunction in Antibody-mediated Rejection.

The pathology-based diagnosis of cardiac antibody-mediated rejection (AMR) relies on the 2013 International Society for Heart and Lung Transplantation Working Formulation, in which microvascular inflammation (MVI) is considered as present or absent regardless of its extent. This work assessed the biological and clinical value of a semiquantitative evaluation of the extent of MVI in endomyocardial biopsies (EMBs). We retrospectively graded the extent of MVI in 291 EMB from 291 patients according to a 4-point scale in which MVI scores of 0, 1, 2, and 3 represented 0%, 1%-10%, 11%-50%, and >50% of the myocardial area, respectively. We analyzed the association between the MVI score and tissue rejection molecular activity assessed by microarrays or reverse transcriptase multiplex ligation-dependent probe amplification, current pathology classification (pathologic AMR [pAMR]), anti-HLA donor-specific antibodies, and graft dysfunction. Overall, 172 (59.1%), 33 (11.4%), 42 (14.4%), and 44 (15.1%) EMB were given MVI scores of 0, 1, 2, and 3, respectively. pAMR1(H+) and pAMR2/3 categories were found to be heterogeneous in terms of MVI score. Acute cellular rejection grades did not influence the MVI score. In both molecular approaches, we observed a stepwise increase in the expression of AMR-related transcripts with increasing MVI scores, independent of the C4d or CD68 status (P < 0.001). Both the frequency and mean fluorescence intensity of donor-specific antibodies gradually increased with the MVI score (P < 0.001). Acute graft dysfunction was more frequent in MVI score 3 (P < 0.001). The intensity of MVI in EMB, based on a semiquantitative evaluation of its extent, has biological and clinical importance.

Cellular and Molecular Crosstalk of Graft Endothelial Cells During AMR: Effector Functions and Mechanisms.

Graft endothelial cell (EC) injury is central to the pathogenesis of antibody-mediated rejection (AMR). The ability of donor-specific antibodies (DSA) to bind C1q and activate the classical complement pathway is an efficient predictor of graft rejection highlighting complement-dependent cytotoxicity as a key process operating during AMR. In the past 5 y, clinical studies further established the cellular and molecular signatures of AMR revealing the key contribution of other, IgG-dependent and -independent, effector mechanisms mediated by infiltrating NK cells and macrophages. Beyond binding to alloantigens, DSA IgG can activate NK cells and mediate antibody-dependent cell cytotoxicity through interacting with Fcγ receptors (FcγRs) such as FcγRIIIa (CD16a). FcRn, a nonconventional FcγR that allows IgG recycling, is highly expressed on ECs and may contribute to the long-term persistence of DSA in blood. Activation of NK cells and macrophages results in the production of proinflammatory cytokines such as TNF and IFNγ that induce transient and reversible changes in the EC phenotype and functions promoting coagulation, inflammation, vascular permeability, leukocyte trafficking. MHC class I mismatch between transplant donor and recipient can create a situation of "missing self" allowing NK cells to kill graft ECs. Depending on the microenvironment, cellular proximity with ECs may participate in macrophage polarization toward an M1 proinflammatory or an M2 phenotype favoring inflammation or vascular repair. Monocytes/macrophages participate in the loss of endothelial specificity in the process of endothelial-to-mesenchymal transition involved in renal and cardiac fibrosis and AMR and may differentiate into ECs enabling vessel and graft (re)-endothelialization.

Donor-Transmitted Atherosclerosis and the Occurrence of Cardiac Antibody-Mediated Rejection Influenced on the Development of Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is still a major cause of mortality in heart transplant (HTx) recipients. Risk stratification for predicting the development of CAV is needed to suppress the development of CAV. Our aim of this study is to clarify the risk factors for the development of CAV. We retrospectively reviewed consecutive 100 HTx recipients who did not have any coronary artery lesions on first coronary angiography at 5 to 12 weeks after transplantation (baseline). Donor-transmitted atherosclerosis (DA) on intravascular ultrasound (IVUS) was defined as a maximal intimal thickness of 0.5 mm or greater at baseline. Pathology diagnosis of cardiac antibody-mediated rejection (pAMR) was pathologically diagnosed on the basis of the 2013 ISHLT working formulation. The development of CAV included the any coronary revascularization, acute myocardial infarction and the coronary artery lesions classified ISHLT CAV 1 or 2. DA on IVUS was observed in 62 recipients regardless of no apparent lesions on angiography. pAMR was diagnosed in six recipients within 1year post-HTx. Sixteen recipients had the development of CAV, including five who underwent revascularization, one who had acute myocardial infarction and three who found the moderate lesions classified ISHLT CAV2. DA and the occurrence of pAMR within 1 year post-HTx significantly influenced on the cumulative incidence of development of CAV at a mean follow up period of 6.7±4.6 years after transplantation [Hazard ratio (HR): 5.2, 95% confidence intervals (CI):1.2-23.0, P=0.029 and HR: 7.3, 95% CI:2.0-26.7, P=0.003, respectively]. Multivariable cox proportional hazard model including DA, the occurrence of pAMR and associated variables with the development of CAV showed that DA and the occurrence of pAMR were independently associated with the development of CAV (HR: 5.4, 95%CI:1.2-24.6, P=0.028 and HR: 6.7, 95%CI:1.5-29.1, P=0.012, respectively). DA and the occurrence of pAMR within 1 year post-HTx independently influenced on the development of CAV.

The impact of asymptomatic antibody-mediated rejection on outcome after heart transplantation.

Defining criteria for antibody-mediated rejection (AMR) in heart transplantation were standardized a few years ago, but very little is known about asymptomatic cardiac AMR. We will start the review with a background summarizing the timeline of cardiac AMR. Then we will cover past and current knowledge about asymptomatic cardiac AMR and its impact on outcome after transplantation, with added insight from experience with other solid-organ transplants. The incidence of asymptomatic cardiac AMR had likely been under-estimated because biopsy surveillance for it in the absence of clinical manifestation was not the norm. Recent data indicate that it may be more common especially when counting concomitant acute cellular rejection (mixed rejection). Also a higher risk of cardiac allograft vasculopathy (CAV) and cardiovascular mortality have been linked to it. The primary implication of these findings is whether therapeutic intervention is warranted, but the appropriate target patient population likely to benefit from treatment is yet to be determined. Asymptomatic cardiac AMR is not uncommon and it negatively impacts outcome after heart transplantation.

Tocilizumab for Antibody-Mediated Rejection in the Setting of Cardiac Allograft Vasculopathy

Introduction IL-6 is a pro-inflammatory cytokine that potentiates the effect of plasma cells, immunoglobulins, T-cells, and macrophages. IL-6 levels are associated with atherosclerotic plaque progression and graft fibrosis; IL-6 blockade may have a role in therapy for cardiac allograft vasculopathy (CAV). Preclinical data has also implicated IL-6 signaling in graft rejection. Tocilizumab, an IL-6 receptor antagonist, has successfully decreased donor-specific antibodies (DSAs) in renal transplant patients with antibody-mediated rejection (AMR). Herein, we report on the use of tocilizumab in a heart transplant recipient with treatment-refractory AMR and established CAV. Case Report A 65 year old male who underwent heart transplantation 13 years ago presented with dyspnea. His history was significant for AMR 5 years post-transplant and CAV 10 years post-transplant. On admission, studies revealed reduced LV ejection fraction (LVEF, 70% to 50%) and cardiac index (CI, 1.27 L/min/m2), severe 3-vessel CAV, and elevated pulmonary capillary wedge pressure (PCWP, 28 mmHg). He had new DSAs against HLA-A, -B, -DQ, and -DR antigens (MFI 5,792-24,748); biopsy grade was 1R/1A. He was treated with steroids, plasmapheresis, IVIg, and rituximab; maintenance immunosuppression was revised to tacrolimus, everolimus, mycophenolate, and prednisone. He was readmitted twice within the next month with acute decompensation requiring inotropes. He had a further decline in LVEF to 45%, CAV progression, and largely unchanged DSAs. He was again treated with steroids, plasmapheresis, and IVIg. Given progressive decline despite traditional AMR and CAV therapy, we initiated tocilizumab 800 mg monthly. He has received tocilizumab for one year without significant complications or hospitalizations; he reports NYHA class II symptoms. HLA screen showed resolution of HLA-A, -B, and -DR DSAs and MFI reduction of HLA-DQ DSA (24,748 to 14,994). Right heart catheterization was significantly improved (CI 2.06 L/min/m2 and PCWP 18 mmHg); LVEF remains unchanged and coronary angiography shows CAV progression. Summary To our knowledge, this represents the first report of using tocilizumab for refractory cardiac AMR and CAV. Additional studies are warranted to evaluate the safety and efficacy of tocilizumab in heart transplant recipients and to elucidate the mechanism of DSA clearance by tocilizumab. IL-6 is a pro-inflammatory cytokine that potentiates the effect of plasma cells, immunoglobulins, T-cells, and macrophages. IL-6 levels are associated with atherosclerotic plaque progression and graft fibrosis; IL-6 blockade may have a role in therapy for cardiac allograft vasculopathy (CAV). Preclinical data has also implicated IL-6 signaling in graft rejection. Tocilizumab, an IL-6 receptor antagonist, has successfully decreased donor-specific antibodies (DSAs) in renal transplant patients with antibody-mediated rejection (AMR). Herein, we report on the use of tocilizumab in a heart transplant recipient with treatment-refractory AMR and established CAV. A 65 year old male who underwent heart transplantation 13 years ago presented with dyspnea. His history was significant for AMR 5 years post-transplant and CAV 10 years post-transplant. On admission, studies revealed reduced LV ejection fraction (LVEF, 70% to 50%) and cardiac index (CI, 1.27 L/min/m2), severe 3-vessel CAV, and elevated pulmonary capillary wedge pressure (PCWP, 28 mmHg). He had new DSAs against HLA-A, -B, -DQ, and -DR antigens (MFI 5,792-24,748); biopsy grade was 1R/1A. He was treated with steroids, plasmapheresis, IVIg, and rituximab; maintenance immunosuppression was revised to tacrolimus, everolimus, mycophenolate, and prednisone. He was readmitted twice within the next month with acute decompensation requiring inotropes. He had a further decline in LVEF to 45%, CAV progression, and largely unchanged DSAs. He was again treated with steroids, plasmapheresis, and IVIg. Given progressive decline despite traditional AMR and CAV therapy, we initiated tocilizumab 800 mg monthly. He has received tocilizumab for one year without significant complications or hospitalizations; he reports NYHA class II symptoms. HLA screen showed resolution of HLA-A, -B, and -DR DSAs and MFI reduction of HLA-DQ DSA (24,748 to 14,994). Right heart catheterization was significantly improved (CI 2.06 L/min/m2 and PCWP 18 mmHg); LVEF remains unchanged and coronary angiography shows CAV progression. To our knowledge, this represents the first report of using tocilizumab for refractory cardiac AMR and CAV. Additional studies are warranted to evaluate the safety and efficacy of tocilizumab in heart transplant recipients and to elucidate the mechanism of DSA clearance by tocilizumab.

Relative Frequencies of Alloantigen-Specific Helper CD4 T Cells and B Cells Determine Mode of Antibody-Mediated Allograft Rejection.

Humoral alloimmunity is now recognized as a major determinant of transplant outcome. MHC glycoprotein is considered a typical T-dependent antigen, but the nature of the T cell alloresponse that underpins alloantibody generation remains poorly understood. Here, we examine how the relative frequencies of alloantigen-specific B cells and helper CD4 T cells influence the humoral alloimmune response and how this relates to antibody-mediated rejection (AMR). An MHC-mismatched murine model of cardiac AMR was developed, in which T cell help for alloantibody responses in T cell deficient (Tcrbd−/−) C57BL/6 recipients against donor H-2Kd MHC class I alloantigen was provided by adoptively transferred “TCR75” CD4 T cells that recognize processed H-2Kd allopeptide via the indirect-pathway. Transfer of large numbers (5 × 105) of TCR75 CD4 T cells was associated with rapid development of robust class-switched anti-H-2Kd humoral alloimmunity and BALB/c heart grafts were rejected promptly (MST 9 days). Grafts were not rejected in T and B cell deficient Rag2−/− recipients that were reconstituted with TCR75 CD4 T cells or in control (non-reconstituted) Tcrbd−/− recipients, suggesting that the transferred TCR75 CD4 T cells were mediating graft rejection principally by providing help for effector alloantibody responses. In support, acutely rejecting BALB/c heart grafts exhibited hallmark features of acute AMR, with widespread complement C4d deposition, whereas cellular rejection was not evident. In addition, passive transfer of immune serum from rejecting mice to Rag2−/− recipients resulted in eventual BALB/c heart allograft rejection (MST 20 days). Despite being long-lived, the alloantibody responses observed at rejection of the BALB/c heart grafts were predominantly generated by extrafollicular foci: splenic germinal center (GC) activity had not yet developed; IgG secreting cells were confined to the splenic red pulp and bridging channels; and, most convincingly, rapid graft rejection still occurred when recipients were reconstituted with similar numbers of Sh2d1a−/− TCR75 CD4 T cells that are genetically incapable of providing T follicular helper cell function for generating GC alloimmunity. Similarly, alloantibody responses generated in Tcrbd−/− recipients reconstituted with smaller number of wild-type TCR75 CD4 T cells (103), although long-lasting, did not have a discernible extrafollicular component, and grafts were rejected much more slowly (MST 50 days). By modeling antibody responses to Hen Egg Lysozyme protein, we confirm that a high ratio of antigen-specific helper T cells to B cells favors development of the extrafollicular response, whereas GC activity is favored by a relatively high ratio of B cells. In summary, a relative abundance of helper CD4 T cells favors development of strong extrafollicular alloantibody responses that mediate acute humoral rejection, without requirement for GC activity.This work is composed of two parts, of which this is Part I. Please read also Part II: Chhabra et al., 2019.

Abstract 17377: The Effect of Mechanical Circulatory Support on HLA Antibodies and Antibody-Mediated Rejection in Cardiac Allografts

Introduction: Due to the shortage of donor organs, mechanical circulatory support systems (MCS) are now widely used as a treatment option to bridge the failing heart to transplant. It has been observed that MCS patients show a higher frequency of antibody-mediated rejection (AMR) episodes. The latter is thought to represent an immune reaction directed against the device in terms of allosensitation. Hypothesis: Capillary C4d and/or C3d depositions are required to diagnose AMR in cardiac allografts. We aimed to analyze the effect of MCS on pre- and post-HTx HLA antibodies and their correlation to cardiac AMR with due regards to capillary C3d and C4d depositions. Methods: We evaluated all consecutive right ventricular protocol endomyocardial biopsies (EMBs) of cardiac allografts which fulfilled the ISHLT- criteria (254 patients) during two consecutive calendar years. With regards to pre- transplant MCS treatment patients were divided into two groups (MCS group n=82 patients, non MCS group n= 138 patients). Conventional histology and immunohistochemical stains were used on formalin-fixed paraffin-embedded tissue sections (FFPE) to evaluate the EMBs regarding AMR (complements C3d and C4d). Permutation test (x 2 ) was performed to analyze the relationship between C4d and C3d and pre-and post-transplant HLA-antibodies, measured using Luminex assay, in all patient subgroups. Cochran-Mantel-Haenzsel was performed to assure the significance of the difference of interactions in both tables. Results: The statistical analysis showed in the MCS group a highly significant positive correlation between C3d and Pre-Tx-HLA (p=0.012, Pre-Tx-HLA Class I and II p= 0.042, respectively vs p=0.884 and p=0.349 in non-MCS group), which levelled out following HTx (p= 0.867 and 0.697 for HLA Class I and II, vs p=0.212 and p=0.682 in non-MCS group, respectively). Statistical significance was not reached between C4d and pre-or post Tx HLA-antibodies in any group (p=0.349 vs. p=0.694 for entire study population). Conclusions: We demonstrated that C3d correlates solely in the MCS group with pre-Tx HLA antibodies and could therefore add to the diagnosis of AMR if the pre-transplant treatment is being considered in the diagnostic setting.

Routine C4d immunohistochemistry in cardiac allografts: Long-term outcomes

In the past decade, C4d has emerged as a potential marker for antibody-mediated rejection (AMR); however, evidence on its use as a prognostic tool has been controversial. Although the International Society for Heart and Lung Transplantation guideline recommends early routine surveillance of C4d in heart transplantation, there is no consensus on its value in the pathologic assessment of AMR. Herein we present a correlation analysis of C4d immunoreactivity in endomyocardial biopsies with clinical cardiac dysfunction, cellular rejection, human leukocyte antigen (HLA) status, cardiac allograft vasculopathy (CAV) and death. A total of 5,840 endomyocardial biopsies from 296 heart transplant recipients (January 2004 to December 2014) were stained prospectively for C4d. Strong, diffuse endothelial staining was considered positive. All patients had at least 1 year of follow-up. Positive C4d staining was present in 53 biopsies from 28 patients. Sixteen of 28 patients had clinically significant cardiac dysfunction at the time of positive biopsy. In C4d-positive patients, the mean panel-reactive antibody (PRA) level was 33%. Ten patients demonstrated a first C4d positivity within the first year post-transplant, whereas 18 patients had C4d positivity after 1 year post-transplant. At autopsy, all 11 C4d-positive patients examined demonstrated cardiac allograft vasculopathy (CAV) as the underlying cause of death. In contrast, only 2 of 8 (25%) C4d-negative patients had CAV at autopsy. In the surviving cohort, there was an angiographic diagnosis of higher-than-moderate CAV in 10 patients (3.8%). C4d-positive patients contributed to 67% of the overall institutional mortality in heart transplant recipients. Late C4d positivity (>1 year post-transplant) demonstrated an even higher risk for developing CAV and poor prognosis than early C4d positivity (within 1 year). In the C4d-negative group with postmortem examination, 75% (6 of 8) deaths were due to non-cardiac causes. Our findings show a positive association of C4d with CAV and death. We identified a prognostic role for C4d in heart transplantation warranting routine long-term detection of this marker in the pathologic evaluation of cardiac AMR.

(342) - Prospective Study of Histopathologic Features of Cardiac Antibody-Mediated Rejection and Correlation with Donor Specific Antibodies and Graft Dysfunction

(342) - Prospective Study of Histopathologic Features of Cardiac Antibody-Mediated Rejection and Correlation with Donor Specific Antibodies and Graft Dysfunction

(343) - Endothelial Cell Activation in a Mouse Model of Cardiac Antibody-Mediated Rejection

(343) - Endothelial Cell Activation in a Mouse Model of Cardiac Antibody-Mediated Rejection

Antibody-mediated Rejection in Heart Transplantation

Heart transplantation is an excellent long-term treatment that confers functionality and longevity in select patients with end-stage heart failure. Yet, allograft rejection continues to pose a significant threat, especially in high-risk recipients and soon after transplantation. Of the two prevailing pathologic types of acute rejection in cardiac allografts, antibody-mediated rejection (AMR) had been variably defined and poorly understood for the past three decades when compared to cellular rejection. As a result, progress in understanding its pathologic and clinical behavior and the ability to find effective therapies had been hindered. Recent years have seen a renewed interest in cardiac AMR with efforts from pathologists, immunologists, and clinicians leading to a standardized diagnostic nomenclature.

Dynamics in Circulating miRNAs Following Heart Transplantation and During Episodes of Cellular and Antibody-Mediated Cardiac Rejection

Heart transplantation (HTx) is the definitive treatment for severe heart failure. Despite universal pharmacologic immunosuppression, allograft rejection is still a significant threat to allograft function and its occurrence is often unpredictable. Novel biomarkers such as circulating microRNAs (miRs) may help in profiling and predicting rejection. Prior studies have examined a limited set of circulating miRs during acute cellular rejection (ACR) following HTx but no data exist on circulating miRs in antibody-mediated rejection (AMR).

Late Antibody-Mediated Rejection (AMR) in Heart Transplantation: How “Late” Is It?

Late Antibody-Mediated Rejection (AMR) in Heart Transplantation: How “Late” Is It?

Rituximab is associated with improved survival in cardiac allograft patients with antibody‐mediated rejection: a single center review

Antibody-mediated rejection (AMR) after cardiac transplantation is associated with significant mortality, and the optimal treatment of this condition is poorly defined. Rituximab has been used successfully for the treatment for antibody-mediated diseases; however, its role in AMR is unclear. We review our experience with rituximab in patients with cardiac allograft AMR. We conducted a retrospective analysis of cardiac transplant patients with a diagnosis of AMR from 2001 to 2011. Inclusion criteria were clinical suspicion of rejection with the presence of C4d complement staining on endomyocardial biopsy and the absence of cellular rejection of grade 2R or greater. Patients were divided into Rituximab and NoRituximab groups. The primary endpoint was all-cause mortality. Secondary endpoints were infection, change in ejection fraction (EF), and rehospitalization. Thirty-three patients met inclusion criteria, of whom 13 received rituximab and 20 did not. Baseline characteristics were similar between groups. Kaplan-Meier curves for a three-yr follow-up period demonstrate improved survival in the Rituximab group (p = 0.0089). There were no differences in secondary endpoints. We found that rituximab therapy was associated with improved survival in cardiac allograft AMR. Further prospective, randomized studies in larger patient populations are needed to confirm this finding and to define ideal timing for rituximab administration.

Late Antibody-Mediated Rejection After Heart Transplantation Following the Development of De Novo Donor-Specific Human Leukocyte Antigen Antibody

Antibody-mediated rejection (AMR) is an important problem after heart transplantation. Most cases seem to occur in sensitized recipients with preformed donor-specific human leukocyte antigen antibody (DSA) early after transplantation. Few data exist on AMR in patients who form de novo DSA. We describe the clinical features and treatment outcome for late AMR secondary to de novo DSA. This was a retrospective, observational cohort study. All heart transplant patients treated for symptomatic AMR secondary to de novo DSA between November 2005 and August 2011. Fifteen patients were treated for AMR giving an incidence of 3.1 cases per 1000 person years and a prevalence of 1.4%. All had evidence of heart failure on presentation and de novo DSA at diagnosis. There was a spectrum of histologic and immunohistochemical findings. Despite treatment with immunepheresis, intravenous immunoglobulin, and rituximab, and in some cases total lymph node irradiation (n=3) and bortezomib (n=2), clinical outcomes were poor. DSA antibody levels, measured using Labscreen single antigen kits, were reduced by a mean of 76% with a median of 77% and a range of 35% to 99%, but were not eliminated. Forty-six percent had persistent cardiac allograft dysfunction. Mean and median survival was 1.3 and 0.8 years after diagnosis of AMR. Only 40% were alive at the end of the study period. Late cardiac AMR caused by de novo DSA was an uncommon but serious problem. Despite treatment consistent with current best practice, 46% of patients developed persistent cardiac dysfunction and their medium-term survival was poor.