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The choice between Basiliximab (BSX) or Anti-Thymocyte Globulin (ATG) as induction therapy in non-immunized kidney transplant recipients remains uncertain. Whilst ATG may allow steroid withdrawal and a decrease in tacrolimus, it also increases infectious complications. We investigated outcomes in non-immunized patients receiving a very low dosage of ATG versus BSX as induction. Study outcomes were patient/graft survival, cumulative probabilities of biopsy proven acute rejection (BPAR), infectious episode including CMV and post-transplant diabetes (PTD). Cox, logistic or linear statistical models were used depending on the studied outcome and models were weighted on propensity scores. 100 patients received ATG (mean total dose of 2.0 mg/kg) and 83 received BSX. Maintenance therapy was comparable. Patient and graft survival did not differ between groups, nor did infectious complications. There was a trend for a higher occurrence of a first BPAR in the BSX group (HR at 1.92; 95%CI: [0.77; 4.78]; p = 0.15) with a significantly higher BPAR episodes (17% vs 7.3%, p = 0.01). PTD occurrence was significantly higher in the BSX group (HR at 2.44; 95%CI: [1.09; 5.46]; p = 0.03). Induction with a very low dose of ATG in non-immunized recipients was safe and associated with a lower rate of BPAR and PTD without increasing infectious complications.
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Soro Antilinfocitário , Transplante de Rim , Humanos , Basiliximab , Soro Antilinfocitário/uso terapêutico , Imunossupressores/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Rejeição de Enxerto , Sobrevivência de Enxerto , TransplantadosRESUMO
MOTIVATION: The HLA system plays a pivotal role in both clinical applications and immunology research. Typing HLA genes in patient and donor is indeed required in hematopoietic stem cell and solid-organ transplantation, and the histocompatibility complex region exhibits countless genetic associations with immune-related pathologies. Since the discovery of HLA antigens, the HLA system nomenclature and typing methods have constantly evolved, which leads to difficulties in using data generated with older methodologies. RESULTS: Here, we present Easy-HLA, a web-based software suite designed to facilitate analysis and gain knowledge from HLA typing, regardless of nomenclature or typing method. Easy-HLA implements a computational and statistical method of HLA haplotypes inference based on published reference populations containing over 600 000 haplotypes to upgrade missing or partial HLA information: 'HLA-Upgrade' tool infers high-resolution HLA typing and 'HLA-2-Haplo' imputes haplotype pairs and provides additional functional annotations (e.g. amino acids and KIR ligands). We validated both tools using two independent cohorts (total n = 2500). For HLA-Upgrade, we reached a prediction accuracy of 92% from low- to high-resolution of European genotypes. We observed a 96% call rate and 76% accuracy with HLA-2-Haplo European haplotype pairs prediction. In conclusion, Easy-HLA tools facilitate large-scale immunogenetic analysis and promotes the multi-faceted HLA expertise beyond allelic associations by providing new functional immunogenomics parameters. AVAILABILITY AND IMPLEMENTATION: Easy-HLA is a web application freely available (free account) at: https://hla.univ-nantes.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Antígenos HLA , Alelos , Genótipo , Haplótipos , Teste de Histocompatibilidade , HumanosRESUMO
BACKGROUND: Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. OBJECTIVE: To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals. METHODS: We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma. RESULTS: Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10-4; weighted effect size, 0.51 [0.15-0.87]). CONCLUSIONS: We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.
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Alelos , Negro ou Afro-Americano/genética , Cadeias HLA-DRB1/genética , Imunoglobulina E/imunologia , Polimorfismo de Nucleotídeo Único , Asma , Feminino , Cadeias HLA-DRB1/imunologia , Humanos , MasculinoRESUMO
HLA-B*15:648 differs from HLA-B*15:02:01:01 by one nucleotide substitution in codon 77 in exon 2.
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Genes MHC Classe I , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Alelos , Éxons/genética , Antígenos HLA-B/genéticaRESUMO
Forty-three novel HLA-H alleles, including 32 identified in cohorts of French donors for Hematopoietic Stem Cell Transplantation, have been characterized by Next-Generation Sequencing (NGS) using a long range PCR approach. A phylogenetic study confirms three main HLA-H clades.
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Transplante de Células-Tronco Hematopoéticas , Doadores de Tecidos , Humanos , Alelos , Filogenia , Sequenciamento de Nucleotídeos em Larga Escala , Teste de HistocompatibilidadeRESUMO
Loss of heterozygosity or HLA loss is a genomic-type escape mechanism highlighted in certain types of relapses after allogeneic hematopoietic stem cell transplantation with a non-HLA identical donor, and especially after haplo-identical transplantation. The diagnosis must be made with certainty because the result conditions the therapy. In this article, the different mechanisms and techniques that can be used for the diagnosis of loss of heterozygosity, as well as the therapeutic options are reviewed, making it possible to establish clinico-biological recommendations for the diagnosis confirmation and management of the patients in relapse.
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Transplante de Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Humanos , Sociedades Médicas , RecidivaRESUMO
HLA-DQA1*04:14N differs from HLA-DQA1*04:01:01:03 by a single nucleotide deletion in codon 113 in exon 3.
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Alelos , Éxons , Cadeias alfa de HLA-DQ , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Cadeias alfa de HLA-DQ/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Códon , Sequência de Bases , Análise de Sequência de DNA/métodos , Deleção de SequênciaRESUMO
Introduction: Polymorphisms in the KIR and HLA genes contribute to the diversity of the NK cell repertoire. Extrinsic factors also play a role in modifying this repertoire. The best example is cytomegalovirus, which promotes the expansion of memory-like NK cells. However, the mechanisms governing this phenotypic structure are poorly understood. Furthermore, the influence of age and sex has been understudied. Methods: In this study, we examined these parameters in a cohort of 200 healthy volunteer blood donors, focusing on the major inhibitory KIR receptors and CD94/NKG2A, as well as the differentiation marker CD57 and the memory-like population marker NKG2C. Flow cytometry and two joint analyses, unsupervised and semi-supervised, helped define the impact of various intrinsic and extrinsic markers on the phenotypic structure of the NK cell repertoire. Results: In the KIR NK cell compartment, the KIR3DL1 gene is crucial, as unexpressed alleles lead to a repertoire dominated by KIR2D interacting only with HLA-C ligands, whereas an expressed KIR3DL1 gene allows for a greater diversity of NK cell subpopulations interacting with all HLA class I ligands. KIR2DL2 subsequently favors the KIR2D NK cell repertoire specific to C1/C2 ligands, whereas its absence promotes the expression of KIR2DL1 specific to the C2 ligand. The C2C2Bw4+ environment, marked by strong -21T motifs, favors the expansion of the NK cell population expressing only CD57, whereas the absence of HLA-A3/A11 ligands favors the population expressing only NKG2A, a population highly represented within the repertoire. The AA KIR genotype favors NK cell populations without KIR and NKG2A receptors, whereas the KIR B+ genotypes favor populations expressing KIR and NKG2A. Interestingly, we showed that women have a repertoire enriched in CD57- NK cell populations, while men have more CD57+ NK cell subpopulations. Discussion: Overall, our data demonstrate that the phenotypic structure of the NK cell repertoire follows well-defined genetic rules and that immunological history, sex, and age contribute to shaping this NK cell diversity. These elements can contribute to the better selection of hematopoietic stem cell donors and the definition of allogeneic NK cells for cell engineering in NK cell-based immunotherapy approaches.cters are displayed correctly.
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Infecções por Citomegalovirus , Citomegalovirus , Genótipo , Células Matadoras Naturais , Receptores KIR , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Feminino , Masculino , Adulto , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/genética , Citomegalovirus/imunologia , Receptores KIR/genética , Pessoa de Meia-Idade , Fatores Sexuais , Fatores Etários , Antígenos CD57 , Teste de Histocompatibilidade , Adulto Jovem , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Antígenos HLA/genética , Antígenos HLA/imunologia , Idoso , Receptores KIR3DL1/genéticaRESUMO
Changing practices and the limited use of cord blood units as a source of cells for allogeneic hematopoietic stem cell transplants (HSC) led us to reconsider the recommendations established in 2011 and 2012, and to propose an update incorporating recent bibliographic data. If HLA compatibility was until now established at low resolution for HLA-A and B loci, and at high resolution for HLA-DRB1, the recent papers are converging towards an increase in the level of resolution, making way for a compatibility now defined in high resolution for all the considered loci, and the inclusion of the HLA-C locus, in order to establish a level of HLA compatibility on 8 alleles (HLA-A, B, C and DRB1). The CD34+ dose is a determining factor in hematopoietic reconstitution but it is not correlated with the total nucleated cells content. This is why we recommend taking these two data into account when choosing a cord blood unit. The recommendations established by our group are presented as a flow chart taking into account the characteristics of the underlying pathology (malignant or non-malignant), the cell dose and the HLA compatibility criteria, as well as criteria linked to the banks in which units are stored.
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HLA-A*33:246 differs from HLA-A*33:01:01:01 allele by one nucleotide substitution in codon 135 in exon 3.
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Introduction: The human immune system contains cells with either effector/memory or regulatory functions. Besides the well-established CD4+CD25hiCD127lo regulatory T cells (Tregs), we and others have shown that B cells can also have regulatory functions since their frequency and number are increased in kidney graft tolerance and B cell depletion as induction therapy may lead to acute rejection. On the other hand, we have shown that CD28-CD8+ T cells represent a subpopulation with potent effector/memory functions. In the current study, we tested the hypothesis that kidney allograft rejection may be linked to an imbalance of effector/memory and regulatory immune cells. Methods: Based on a large cohort of more than 1000 kidney graft biopsies with concomitant peripheral blood lymphocyte phenotyping, we investigated the association between kidney graft rejection and the percentage and absolute number of circulating B cells, Tregs, as well as the ratio of B cells to CD28-CD8+ T cells and the ratio of CD28-CD8+ T cells to Tregs. Kidney graft biopsies were interpreted according to the Banff classification and divided into 5 biopsies groups: 1) normal/subnormal, 2) interstitial fibrosis and tubular atrophy grade 2/3 (IFTA), 3) antibody-mediated rejection (ABMR), 4) T cell mediated-rejection (TCMR), and 5) borderline rejection. We compared group 1 with the other groups as well as with a combined group 3, 4, and 5 (rejection of all types) using multivariable linear mixed models. Results and discussion: We found that compared to normal/subnormal biopsies, rejection of all types was marginally associated with a decrease in the percentage of circulating B cells (p=0.06) and significantly associated with an increase in the ratio of CD28-CD8+ T cells to Tregs (p=0.01). Moreover, ABMR, TCMR (p=0.007), and rejection of all types (p=0.0003) were significantly associated with a decrease in the ratio of B cells to CD28-CD8+ T cells compared to normal/subnormal biopsies. Taken together, our results show that kidney allograft rejection is associated with an imbalance between immune cells with effector/memory functions and those with regulatory properties.
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Linfócitos B Reguladores , Linfócitos T Reguladores , Humanos , Aloenxertos/metabolismo , Anticorpos/metabolismo , Linfócitos B Reguladores/metabolismo , Biópsia , Antígenos CD28 , Linfócitos T CD8-Positivos , Rim/patologiaRESUMO
The novel HLA-DRB1*03:190 allele was characterized using two next generation sequencing technologies.
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Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Cadeias HLA-DRB1/genética , HumanosRESUMO
The novel HLA-C*06:312 allele was characterized using two next generation sequencing technologies.
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Genes MHC Classe I , Antígenos HLA-C , Alelos , Antígenos HLA-C/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
The novel HLA-B*42:01:05 allele was characterized using two next generation sequencing technologies.
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Antígenos HLA-B , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genes MHC Classe I , Antígenos HLA-B/genética , HumanosRESUMO
The HLA system plays a pivotal role both in transplantation and immunology. While classical HLA genotypes matching is made at the allelic level, recent progresses were developed to explore antibody-antigen recognition by studying epitopes. Donor to recipient matching at the epitopic level is becoming a trending topic in the transplantation research field because anti-HLA antibodies are epitope-specific rather than allele-specific. Indeed, different HLA alleles often share common epitopes. We present the HLA-Epi tool (hla.univ-nantes.fr) to study an HLA genotype at the epitope level. Using the international HLA epitope registry (Epregistry.com.br) as a reference, we developed HLA-Epi to easily determine epitopic and allelic compatibility levels between several HLA genotypes. The epitope database covers the most common HLA alleles (N = 2976 HLA alleles), representing more than 99% of the total observed frequency of HLA alleles. The freely accessible web tool HLA-Epi calculates an epitopic mismatch load between different sets of potential recipient-donor pairs at different resolution levels. We have characterized the epitopic mismatches distribution in a cohort of more than 10,000 kidney transplanted pairs from European ancestry, which showed low number of epitopic mismatches: 56.9 incompatibilities on average. HLA-Epi allows the exploration of epitope pairing matching to better understand epitopes contribution to immune responses regulation, particularly during transplantation. This free and ready-to-use bioinformatics tool not only addresses limitations of other related tools, but also offers a cost-efficient and reproducible strategy to analyze HLA epitopes as an alternative to HLA allele compatibility. In the future, this could improve sensitization prevention for allograft allocation decisions and reduce the risk of alloreactivity.
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Rejeição de Enxerto , Antígenos HLA , Alelos , Epitopos , Fluprednisolona/análogos & derivados , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , IsoanticorposRESUMO
The novel HLA-DRB1*04:334 allele was characterized using two next-generation sequencing technologies.
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Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Cadeias HLA-DRB1/genética , HumanosRESUMO
The novel HLA-A*01:405 allele was characterized using two next generation sequencing technologies.
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Antígenos HLA-A , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Antígenos HLA-A/genética , HumanosRESUMO
The novel HLA-A*01:406 allele was characterized using two next generation sequencing technologies.
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Antígenos HLA-A , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Antígenos HLA-A/genética , HumanosRESUMO
The novel HLA-C*06:346 allele was characterized using two next generation sequencing technologies.
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Genes MHC Classe I , Antígenos HLA-C , Alelos , Antígenos HLA-C/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
The novel HLA-DRB1*11:296 allele was characterized using two next generation sequencing technologies.