RESUMO
BACKGROUND: Although numerous reports have studied the consequences of human leukocyte antigen (HLA) mismatching in renal transplantation, there are limited and outdated data analyzing this association in thoracic organ transplantation. Therefore, our study reviewed the impact of HLA mismatching at both the total and the loci levels in the modern-era heart-transplant procedure on survival and chronic rejection outcomes. METHODS: We performed a retrospective analysis of adult patients after heart transplant by using the United Network for Organ Sharing database from January 2005-July 2021. Total HLA and HLA-A, HLA-B and HLA-DR mismatches were analyzed. Survival and cardiac allograft vasculopathy were the outcomes of interest during a 10-year follow-up period using Kaplan-Meier curves, log-rank tests and multivariable regression models. RESULTS: A total of 33,060 patients were included in this study. Recipients with a high degree of HLA mismatching had increased incidences of acute organ rejection. There were no significant differences in mortality rates among any of the total or loci level groups. Similarly, there were no significant differences between total HLA mismatch groups in time to first cardiac allograft vasculopathy, though mismatching at the HLA-DR locus was associated with an increased risk of cardiac allograft vasculopathy. CONCLUSION: Our analysis suggests that HLA mismatch is not a significant predictor of survival in the modern era. Overall, the clinical implications of this study provide reassuring data for the continued use of non-HLA-matched donors in an effort to increase the donor pool. If HLA matching is to be considered for heart transplant donor-recipient selection, matching at the HLA-DR locus should take priority due to its association with cardiac allograft vasculopathy.
Assuntos
Insuficiência Cardíaca , Transplante de Coração , Adulto , Humanos , Estudos Retrospectivos , Sobrevivência de Enxerto , Rejeição de Enxerto/epidemiologia , Antígenos HLA-DR , Antígenos HLARESUMO
HLA donor-specific antibodies (DSAs) pre and post transplant increase the risk of antibody-mediated rejection (AMR) and lead to poor graft survival. Increasing data exist to support the involvement of non-HLA antibodies in triggering an immunological response. The development of non-HLA antibodies specific for AT1R is associated with poor clinical outcomes in orthotopic heart transplant recipients. This case presents an investigation of non-HLA antibodies in a 56-year-old female heart transplant recipient diagnosed with AMR in the absence of DSAs.
Assuntos
Transplante de Coração , Transplante de Rim , Feminino , Humanos , Pessoa de Meia-Idade , Autoanticorpos , Antígenos HLA , Rejeição de Enxerto , Transplante de Coração/efeitos adversosRESUMO
Chimerism monitoring after allogenic Hematopoietic Cell Transplantation (allo-HCT) is critical to determine how well donor cells have engrafted and to detect relapse for early therapeutic intervention. The aim of this study was to establish and detect mixed chimerism and minimal residual disease using Next Generation Sequencing (NGS) testing for the evaluation of engraftment and the detection of early relapse after allo-HCT. Our secondary aim was to compare the data with the existing laboratory method based on Short Tandem Repeat (STR) analysis. One hundred and seventy-four DNA specimens from 46 individuals were assessed using a commercially available kit for NGS, AlloSeq HCT NGS (CareDx), and the STR-PCR assay. The sensitivity, precision, and quantitative accuracy of the assay were determined using artificially created chimeric constructs. The accuracy and linearity of the assays were evaluated in 46 post-transplant HCT samples consisting of 28 levels of mixed chimerism, which ranged from 0.3-99.7%. There was a 100% correlation between NGS and STR-PCR chimerism methods. In addition, 100% accuracy was attained for the two external proficiency testing surveys (ASHI EMO). The limit of detection or sensitivity of the NGS assay in artificially made chimerism mixtures was 0.3%. We conducted a review of all NGS chimerism studies published online, including ours, and concluded that NGS-based chimerism analysis using the AlloSeq HCT assay is a sensitive and accurate method for donor-recipient chimerism quantification and minimal residual disease relapse detection in patients after allo-HCT compared to STR-PCR assay.
Assuntos
Quimerismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Sequenciamento de Nucleotídeos em Larga Escala , Recidiva Local de Neoplasia/genética , Doença Crônica , Quimeras de Transplante/genéticaRESUMO
Antibody-Mediated Rejection (AMR) due to donor-specific antibodies (DSA) is associated with poor outcomes after lung transplantation. Currently, there are no guidelines regarding the selection of treatment protocols. We studied how DSA characteristics including titers, C1q, and mean fluorescence intensity (MFI) values in undiluted and diluted sera may predict a response to therapeutic plasma exchange (TPE) and inform patient prognosis after treatment. Among 357 patients consecutively transplanted without detectable pre-existing DSAs between 01/01/16 and 12/31/18, 10 patients were treated with a standardized protocol of five TPE sessions with IVIG. Based on DSA characteristics after treatment, all patients were divided into three groups as responders, partial responders, and nonresponders. Kaplan-Meier Survival analyses showed a statistically significant difference in patient survival between those groups (P = 0.0104). Statistical analyses showed that MFI in pre-TPE 1:16 diluted sera was predictive of a response to standardized protocol (R2 = 0.9182) and patient survival (P = 0.0098). Patients predicted to be nonresponders who underwent treatment with a more aggressive protocol of eight TPE sessions with IVIG and bortezomib showed improvements in treatment response (P = 0.0074) and patient survival (P = 0.0253). Dilutions may guide clinicians as to which patients would be expected to respond to a standards protocol or require more aggressive treatment.
Assuntos
Transplante de Rim , Transplantados , Rejeição de Enxerto , Sobrevivência de Enxerto , Antígenos HLA , Humanos , Isoanticorpos , Pulmão , Troca Plasmática , Estudos RetrospectivosRESUMO
HLA typing in solid organ transplantation (SOT) is necessary for determining HLA-matching status between donor-recipient pairs and assessing patients' anti-HLA antibody profiles. Histocompatibility has traditionally been evaluated based on serologically defined HLA antigens. The evolution of HLA typing and antibody identification technologies, however, has revealed many limitations with using serologic equivalents for assessing compatibility in SOT. The significant improvements to HLA typing introduced by next-generation sequencing (NGS) require an assessment of the impact of this technology on SOT. We have assessed the role of high-resolution 2-field HLA typing (HR-2F) in SOT by retrospectively evaluating NGS-typed pre- and post-SOT cases. HR-2F typing was highly instructive or necessary in 41% (156/385) of the cases. Several pre- and posttransplant scenarios were identified as being better served by HR-2F typing. Five different categories are presented with specific case examples. The experience of another center (Temple University Hospital) is also included, whereby 21% of the cases required HR-2F typing by Sanger sequencing, as supported by other legacy methods, to properly address posttransplant anti-HLA antibody issues.
Assuntos
Antígenos HLA/classificação , Teste de Histocompatibilidade/métodos , Histocompatibilidade , Transplante de Órgãos/métodos , Seleção de Pacientes , Doadores de Tecidos/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Antígenos HLA/genética , Antígenos HLA/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunogenética , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sequência de DNARESUMO
Full-length sequence covers the 5'-untranslated region (UTR), all introns and exons and the 3' UTR.
Assuntos
Genômica , Humanos , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Alelos , Sequência de Bases , Cadeias HLA-DRB3/genética , Análise de Sequência de DNARESUMO
HLA-DPA1*02:03:05 differs from HLA-DPA*02:03:04 by three nucleotide substitution located in exon 3.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Nucleotídeos , Humanos , Alelos , Éxons/genéticaRESUMO
Full-length sequence of HLA-DRB3*03:46 covers the 5'-untranslated region (UTR), all introns and exons and the 3' UTR.
Assuntos
Genômica , Humanos , Sequência de Bases , Cadeias HLA-DRB3/genética , Alelos , Teste de HistocompatibilidadeRESUMO
Full-length sequence of HLA-DPA1*01:115 covers the 5'-untranslated region (UTR), all introns and exons and the 3'-UTR.
Assuntos
Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Alelos , Análise de Sequência de DNARESUMO
HLA-A*32:172 differs from HLA-A*32:01:01:01 by one nucleotide substitution at position 1013, codon 314 located in exon 6.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Nucleotídeos , Humanos , Alelos , Éxons/genética , Antígenos HLA-A/genéticaRESUMO
HLA-DPA1*01:144 differs from HLA-DPA*01:03:01:04 by one nucleotide substitution at position 44, codon-17 located in exon 1.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Alelos , Teste de Histocompatibilidade , CódonRESUMO
Full-length sequence of HLA-DQA1*02:19 covers the 5'-untranslated region (UTR), all introns and exons and the 3' UTR.
Assuntos
Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Sequência de Bases , Alelos , Cadeias alfa de HLA-DQ/genética , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Análise de Sequência de DNARESUMO
HLA-DPA1*02:72 differs from HLA-DPA1*02:02:02:01 by one nucleotide substitution at position 4273, codon 86 located in exon 3.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Alelos , Teste de Histocompatibilidade , Alinhamento de SequênciaRESUMO
Full-length sequence of HLA-DQB1*04:51 covers the 5'-untranslated region (UTR), all introns and exons and the 3'-UTR.
Assuntos
Cadeias beta de HLA-DQ , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genômica , Cadeias beta de HLA-DQ/genética , HumanosRESUMO
A point mutation in Exon 1, 1-3 (ATG>ACG) causes a non-synonymous change to the start codon, which may affect expression.
Assuntos
Cadeias alfa de HLA-DP , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Cadeias alfa de HLA-DP/genética , HumanosRESUMO
Full-length sequence covers the 5'-untranslated region (UTR), all introns and exons, and the 3' UTR.
Assuntos
Genômica , Tecnologia , Regiões 3' não Traduzidas , Alelos , Sequência de Bases , Cadeias HLA-DRB3/genética , Teste de Histocompatibilidade , Humanos , Análise de Sequência de DNARESUMO
Full-length sequence of HLA-C*15:02:03 covers all introns and exons and the 3' UTR.
Assuntos
Antígenos HLA-C , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genômica , Antígenos HLA-C/genética , Humanos , Análise de Sequência de DNARESUMO
Full-length sequence of HLA-C*07:308 covers the 5'-untranslated region (UTR), all introns and exons and the 3' UTR.
Assuntos
Antígenos HLA-C , Sequenciamento de Nucleotídeos em Larga Escala , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Alelos , Sequência de Bases , Genômica , Antígenos HLA-C/genética , Teste de Histocompatibilidade , Humanos , Análise de Sequência de DNARESUMO
Full-length sequence of HLA-DPA1*02:46 covers the 5'-untranslated region (UTR), all introns and exons and the 3' UTR.
Assuntos
Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Regiões 3' não Traduzidas , Alelos , Cadeias alfa de HLA-DP , Humanos , Análise de Sequência de DNARESUMO
OBJECTIVES: Human leucocyte antigen (HLA) mismatch is a known risk factor for renal transplantation; however, there are conflicting and limited data on its ramifications within lung transplantation (LTx). Therefore, our study evaluated the effects of total HLA, HLA-A, -B and -DR mismatches on LTx outcomes. METHODS: We retrospectively examined the United Network for Organ Sharing database for adult patients who had undergone LTx for the first time between January 2005 and July 2021. Total HLA mismatch (0-3, 4, 5 and 6) and HLA locus mismatch (0-1 and 2) were analysed, with the end points of interest being mortality and bronchiolitis obliterans syndrome (BOS) development. RESULTS: Kaplan-Meier curve analysis found a significant difference in both overall survival (n = 27 651; 11 830 events) and BOS development (n = 25 444; 8901 events) for the total number of HLA (P < 0.001, P < 0.001), HLA-A (P < 0.001, P = 0.006) and HLA-DR (P < 0.001, P < 0.001) mismatches. With reference to 0-3 total HLA mismatches, multivariable Cox regression model found that 6 mismatches had an increased risk of mortality (P = 0.002) while 4 (P = 0.010), 5 (P = 0.007) and 6 (P < 0.001) mismatches had an increased risk of BOS. HLA-B mismatch was not associated with an increased mortality (P = 0.975) or BOS risk (P = 0.512). CONCLUSIONS: This study demonstrates a significant relationship between increased HLA mismatches and BOS development, with decreased overall survival only apparent with 6 mismatches. HLA-A and -DR mismatches were associated with an increased risk of mortality and BOS development compared to groups with at least 1 locus match.