Surveillance Endomyocardial Biopsy in the Modern Era Produces Low Diagnostic Yield for Cardiac Allograft Rejection.

BACKGROUND: The changing epidemiology of cardiac allograft rejection has prompted many to question the yield of surveillance endomyocardial biopsy (EMB) in heart transplantation (HT) patients. We sought to determine the yield of EMB in the modern era. METHODS: We evaluated 2597 EMBs in 182 consecutive HT patients who survived to their first EMB. The EMBs were categorized as asymptomatic or clinically driven and were compared based on era of antiproliferative therapy use at our center (early azathioprine era: 1990-2000 vs modern mycophenolate era: 2000-2011). RESULTS: In the modern era, patients had a higher prevalence of risk factors for developing rejection (≥ International Society of Heart and Lung Transplantation grade 2R); however, the frequency of rejection was decreased at all times (0-6 months: 60.2% vs 21.5%, P < 0.001, 6-12 months: 26.8% vs 1.8%, P < 0.001, 12-36 months: 32.3% vs 10.5%, P = 0.006). The yield of asymptomatic EMB decreased in the modern era between 0 and 6 months (10.9% vs 3.12%), 6 to 12 months (17% vs 0%), and years 2 to 3 (6.1% vs 1.5%). In the early era, the odds ratio of rejection during asymptomatic EMB compared to a clinically driven EMB was 0.47 (95% confidence interval, 0.31-0.71) and was decreased in the modern era (0.17 [0.07-0.42], P = 0.04). The probability of detecting rejection on asymptomatic EMB was significantly reduced in the modern era, even after adjustment for tacrolimus and induction therapy (1% vs 8%, P < 0.001). CONCLUSIONS: The clinical yield of surveillance EMB has decreased in the modern era. The EMB in asymptomatic patients longer than 6 months after HT warrants further scrutiny.

In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation.

Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor-recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

Induction immunosuppression for orthotopic heart transplantation: a review.

OBJECTIVES: To describe the appropriateness and safety of induction immunosuppression for patients at risk for fatal rejection, and to describe the safety and effectiveness profiles of the induction regimens available in the United States. DATA SOURCES: MEDLINE/PubMed database, EMBASE database, Google Scholar; references from pertinent articles were also reviewed to identify additional data. STUDY SELECTION: A systematic literature review from January 1, 1980, through June 30, 2008, was performed. Included articles ranged from case series to prospective randomized controlled double-blind placebo-controlled trials that detailed the following topics with respect to induction immunosuppression: risk of fatal rejection, renal sparing, malignancy, OKT3, rabbit or equine antithymocyte globulin, daclizumab, basiliximab, and alemtuzumab. RESULTS: Patients at highest risk for fatal rejection experienced a survival benefit from induction immunosuppression, whereas all other patients experienced no benefit or harm. Most of the early data detail positive experiences with polyclonal antibody regimens. Several newer trials compare the use of polyclonal strategies with the use of anti-CD25 targeted monoclonal antibodies. Few researchers have assessed the usefulness of an anti-CD52 approach. Overall, induction therapy remains a poorly studied and widely variable practice among the major US heart transplant centers. CONCLUSION: At present, the unrestricted use of induction for all patients does not seem prudent. Induction should be individualized for each patient on the basis of a well-designed protocol, careful analysis of the transplant center's demographics, and the effectiveness and safety profiles of the regimens used.