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1.
Int J Immunogenet ; 47(4): 324-328, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32623831

RESUMO

We analysed data from 80 patients who tested positive for SARS-CoV-2 RNA who had previously been HLA typed to support transplantation. Data were combined from two adjacent centres in Manchester and Leeds to achieve a sufficient number for early analysis. HLA frequencies observed were compared against two control populations: first, against published frequencies in a UK deceased donor population (n = 10,000) representing the target population of the virus, and second, using a cohort of individuals from the combined transplant waiting lists of both centres (n = 308), representing a comparator group of unaffected individuals of the same demographic. We report a significant HLA association with HLA- DQB1*06 (53% vs. 36%; p < .012; OR 1.96; 95% CI 1.94-3.22) and infection. A bias towards an increased representation of HLA-A*26, HLA-DRB1*15, HLA-DRB1*10 and DRB1*11 was also noted but these were either only significant using the UK donor controls, or did not remain significant after correction for multiple tests. Likewise, HLA-A*02, HLA-B*44 and HLA-C*05 may exert a protective effect, but these associations did not remain significant after correction for multiple tests. This is relevant information for the clinical management of patients in the setting of the current SARS-CoV-2 pandemic and potentially in risk-assessing staff interactions with infected patients.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Predisposição Genética para Doença/genética , Teste de Histocompatibilidade , Pneumonia Viral/imunologia , Alelos , Infecções por Coronavirus/patologia , Frequência do Gene , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Transplante de Órgãos , Pandemias , Pneumonia Viral/patologia , Transplantados
2.
BMC Bioinformatics ; 21(1): 295, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32640979

RESUMO

BACKGROUND: The human leukocyte antigen (HLA) gene family plays a key role in the immune response and thus is crucial in many biomedical and clinical settings. Utilizing Sanger sequencing, the golden standard technology for HLA typing enables accurate identification of HLA alleles in high-resolution. However, only the commercial software, such as uTYPE, SBT-Assign, and SBTEngine, and very few open-source tools could be applied to perform HLA typing based on Sanger sequencing. RESULTS: We developed a user-friendly, cross-platform and open-source desktop application, known as SOAPTyping, for Sanger-based typing in HLA class I and II alleles. SOAPTyping can produce accurate results with a comprehensible protocol and featured functions. Moreover, SOAPTyping supports a more advanced group-specific sequencing primers (GSSP) module to solve the ambiguous typing results. We used SOAPTyping to analyze 36 samples with known HLA typing from the University of California Los Angeles (UCLA) International HLA DNA Exchange platform and 100 anonymous clinical samples, and the HLA typing results from SOAPTyping are identical to the golden results and 5.5 times faster than commercial software uTYPE, which shows the usability of SOAPTyping. CONCLUSIONS: We introduce the SOAPTyping as the first open-source and cross-platform HLA typing software with the capability of producing high-resolution HLA typing predictions from Sanger sequence data.


Assuntos
Antígenos HLA/genética , Teste de Histocompatibilidade/métodos , Análise de Sequência de DNA , Software , Alelos , Primers do DNA , Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Classe II , Humanos
3.
Am J Kidney Dis ; 76(3): 374-383, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32359820

RESUMO

RATIONALE & OBJECTIVES: Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. STUDY DESIGN: Multicenter case series. SETTING & PARTICIPANTS: We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. FINDINGS: Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. LIMITATIONS: Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. CONCLUSIONS: De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.


Assuntos
Glomerulonefrite Membranosa/imunologia , Antígenos HLA/análise , Transplante de Rim , Complicações Pós-Operatórias/imunologia , Adulto , Idoso , Aloenxertos/imunologia , Europa (Continente)/epidemiologia , Feminino , Glomerulonefrite Membranosa/epidemiologia , Glomerulonefrite Membranosa/etiologia , Glomerulonefrite Membranosa/cirurgia , Teste de Histocompatibilidade , Humanos , Imunossupressores , Isoanticorpos/imunologia , Isoantígenos/imunologia , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Complicações Pós-Operatórias/etiologia , Receptores da Fosfolipase A2/imunologia , Recidiva , Estudos Retrospectivos
4.
Biol Blood Marrow Transplant ; 26(7): e161-e166, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389803

RESUMO

With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P = .01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P = .0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.


Assuntos
Anemia Aplástica/terapia , Transplante de Medula Óssea/métodos , Infecções por Coronavirus/epidemiologia , Criopreservação/métodos , Rejeição de Enxerto/patologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco de Sangue Periférico/métodos , Pneumonia Viral/epidemiologia , Doença Aguda , Adolescente , Adulto , Idoso , Anemia Aplástica/imunologia , Anemia Aplástica/mortalidade , Anemia Aplástica/patologia , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Estados Unidos/epidemiologia , Doadores não Relacionados
5.
Ann Hematol ; 99(7): 1643-1653, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32458063

RESUMO

To explore the incidence, risk factors, and outcomes of central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL) and to compare the differences in CNS relapse between haploidentical donor HSCT (HID-HSCT) and HLA-identical sibling donor HSCT (ISD-HSCT). We performed a retrospective nested case-control study on patients with CNS relapse after allo-HSCT. The cumulative incidence of CNS relapse was 4.06% after allo-HSCT in ALL, with a significantly poor prognosis. The incidence was 3.91% and 5.36% in HID-HSCT and ISD-HSCT, respectively (p = .227). Among the patients with CNS relapse, the overall survival (OS) at 3 years was 56.2 ± 6.8% in the HID-HSCT subgroup and 76.9 ± 10.2% in the ISD-HSCT subgroup (p = .176). The 3-year cumulative incidence of systemic relapse was also comparable between the two subgroups (HID-HSCT, 40.6 ± 7.4%; ISD-HSCT, 13.3 ± 8.7%, respectively, p = .085). Younger age (p = .045), T-ALL (p = .035), hyperleukocytosis at diagnosis (p < .001), advanced disease stage at transplant (p < .001), pre-HSCT CNS involvement (p < .001), and absence of chronic graft vs host disease (cGVHD) (p < .001) were independent risk factors for CNS relapse after allo-HSCT. In conclusion, CNS relapse was a significant complication after allo-HSCT in ALL and was associated with poor prognosis. The incidences and outcomes were comparable between HID-HSCT and ISD-HSCT.


Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/secundário , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Irmãos , Transplante Haploidêntico , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/terapia , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Teste de Histocompatibilidade/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Recidiva , Estudos Retrospectivos , Doadores de Tecidos/estatística & dados numéricos , Transplante Haploidêntico/efeitos adversos , Transplante Haploidêntico/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/estatística & dados numéricos , Resultado do Tratamento , Gêmeos Monozigóticos/estatística & dados numéricos , Adulto Jovem
6.
J Korean Med Sci ; 35(12): e78, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32233158

RESUMO

BACKGROUND: Human leukocyte antigen (HLA) typing is important for transplant patients to prevent a severe mismatch reaction, and the result can also support the diagnosis of various disease or prediction of drug side effects. However, such secondary applications of HLA typing results are limited because they are typically provided in free-text format or PDFs on electronic medical records. We here propose a method to convert HLA genotype information stored in an unstructured format into a reusable structured format by extracting serotype/allele information. METHODS: We queried HLA typing reports from the clinical data warehouse of Seoul National University Hospital (SUPPREME) from 2000 to 2018 as a rule-development data set (64,024 reports) and from the most recent year (6,181 reports) as a test set. We used a rule-based natural language approach using a Python regex function to extract the 1) number of patients in the report, 2) clinical characteristics such as indication of the HLA testing, and 3) precise HLA genotypes. The performance of the rules and codes was evaluated by comparison between the extracted results from the test set and a validation set generated by manual curation. RESULTS: Among 11,287 reports for development set and 1,107 for the test set describing HLA typing for a single patient, iterative rule generation developed 124 extracting rules and 8 cleaning rules for HLA genotypes. Application of these rules extracted HLA genotypes with 0.892-0.999 precision and 0.795-0.998 recall for the five HLA genes. The precision and recall of the extracting rules for the number of patients in a report were 0.997 and 0.994 and those for the clinical variable extraction were 0.997 and 0.992, respectively. All extracted HLA alleles and serotypes were transformed according to formal HLA nomenclature by the cleaning rules. CONCLUSION: The rule-based HLA genotype extraction method shows reliable accuracy. We believe that there are significant number of patients who takes profit when this under-used genetic information will be return to them.


Assuntos
Antígenos HLA/genética , Teste de Histocompatibilidade , Armazenamento e Recuperação da Informação , Processamento de Linguagem Natural , Algoritmos , Data Warehousing , Registros Eletrônicos de Saúde , Genótipo , Humanos , Seul
7.
J Virol ; 94(13)2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32303592

RESUMO

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/virologia , Teste de Histocompatibilidade/métodos , Pneumonia Viral/virologia , Sequência de Aminoácidos , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Epitopos de Linfócito T/imunologia , Variação Genética , Genótipo , Haplótipos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata/imunologia , Pandemias , Pneumonia Viral/imunologia , Linfócitos T/imunologia
8.
Biol Blood Marrow Transplant ; 26(7): 1312-1317, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32283185

RESUMO

The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.


Assuntos
Transplante de Medula Óssea/métodos , Infecções por Coronavirus/epidemiologia , Criopreservação/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Linfoma/terapia , Síndromes Mielodisplásicas/terapia , Pneumonia Viral/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Teste de Histocompatibilidade , Humanos , Leucemia/imunologia , Leucemia/mortalidade , Leucemia/patologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Pandemias , Irmãos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Estados Unidos/epidemiologia , Doadores não Relacionados/provisão & distribução
9.
PLoS One ; 15(4): e0232050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324777

RESUMO

BACKGROUND: Next-generation sequencing (NGS) has enabled efficient high-resolution typing of human leukocyte antigen (HLA) genes with minimal ambiguity. Most commercially available assays amplify individual or subgroup of HLA genes by long-range PCR followed by library preparation and sequencing. The AllType assay simplifies the workflow by amplifying 11 transplant-relevant HLA genes in one PCR reaction. Here, we report the performance of this unique workflow evaluated using 218 genetically diverse samples. METHODS: Five whole genes (HLA-A/B/C/DQA1/DPA1) and six near-whole genes (HLA-DRB1/DRB345/DQB1/DPB1; excluding exon 1 and part of intron 1) were amplified in a multiplexed, long-range PCR. Manual library preparation was performed per manufacturer's protocol, followed by template preparation and chip loading on the Ion Chef, and sequencing on the Ion S5 sequencer. Pre-specified rules for quality control and repeat testing were followed; technologists were blinded to the reference results. The concordance between AllType and reference results was determined at 2-field resolution. We also describe the ranges of input DNA and library concentrations, read number per sample and per locus, and key health metrics in relation to typing results. RESULTS: The concordance rates were 98.6%, 99.8% and 99.9% at the sample (n = 218), genotype (n = 1688), and allele (n = 3376) levels, respectively. Three genotypes were discordant, all of which shared the same G group typing results with the reference. Most ambiguous genotypes (116 out of 144, 80.6%) were due to the lack of exon 1 and intron 1 coverage for HLA-DRB1/DRB345/DQB1/DPB1 genes. A broad range of input DNA concentrations and library concentrations were tolerated. Per sample read numbers were adequate for accurate genotyping. Per locus read numbers showed some inter-lot variations, and a trend toward improved inter-locus balance was observed with later lots of reagents. CONCLUSION: The AllType assay on the Ion Chef/Ion S5 platform offers a robust and efficient workflow for clinical HLA typing at the 2-field resolution. The multiplex PCR strategy simplifies the laboratory procedure without compromising the typing accuracy.


Assuntos
Antígenos HLA/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Humanos , Tipagem de Sequências Multilocus , Reação em Cadeia da Polimerase Multiplex/métodos , Reprodutibilidade dos Testes , Análise de Sequência de DNA/métodos , Doadores de Tecidos , Fluxo de Trabalho
11.
Kidney Int ; 97(4): 653-655, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32200859

RESUMO

The future of HLA matching in solid organ transplantation lies in epitope matching. The article by Sapir-Pichhadze et al. provides indirect evidence that there is a difference in immunogenicity between antibody-verified versus non-verified eplets. However, this difference was less clear for HLA class II, showing the need for additional efforts to identify truly immunogenic HLA class II epitope mismatches.


Assuntos
Transplante de Rim , Transplante de Órgãos , Anticorpos , Epitopos , Teste de Histocompatibilidade
13.
Int J Immunogenet ; 47(2): 139-148, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32034894

RESUMO

DKMS is a leading stem cell donor registry with more than 9 million donors. Donor registry activities share many touch points with topics from immunogenetics or population genetics. In this two-part review article, we deal with these aspects of donor registry work by using the example of DKMS. In the second part of the review, we focus on donor typing of non-HLA genes, the impact of donor age, gender and CMV serostatus on donation probabilities, the identification of novel HLA, KIR and MIC alleles by high-throughput donor typing, the activities of the Collaborative Biobank and pharmacogenetics in the donor registry context.


Assuntos
Antígenos HLA/genética , Sistema de Registros , Células-Tronco/imunologia , Doadores de Tecidos , Alelos , Tipagem e Reações Cruzadas Sanguíneas , Genótipo , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Imunogenética
14.
Transfusion ; 60(5): 940-946, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32086954

RESUMO

BACKGROUND: Patients refractory for platelet transfusions benefit from human leukocyte antigen (HLA)-matched platelet transfusions. Differences in ethnic background of patients and donors could hamper the availability of sufficient numbers of HLA-matched donors for all patients. We evaluated our HLA-matched donor program and explored the role of ethnic background of patients related to the number of available donors. METHODS: We performed a cohort study among consecutive patients who received HLA-matched platelet concentrates in the Netherlands between 1994 and 2017. The number of available matched donors was determined per patient. Haplotypes were constructed from genotypes with computer software (PyPop). Based on haplotypes, HaploStats, an algorithm from the National Marrow Donor Program, was used to assess the most likely ethnic background for patients with 5 or fewer and 30 or more donors. RESULTS: HLA typing was available for 19,478 donors in September 2017. A total of 1206 patients received 12,350 HLA-matched transfusions. A median of 83 (interquartile range, 18-266) donors were available per patient. For 95 (10.3%) patients, 5 or fewer donors were available. These patients were more likely to have an African American background, whereas patients with 30 or more donors were more often from Caucasian origin, compared with Caucasian origin for patients with 30 donors. CONCLUSION: Adequate transfusion support could be guaranteed for most but not all refractory patients. More non-Caucasian donors are required to ensure the availability of HLA-matched donors for all patients in the Netherlands.


Assuntos
Doadores de Sangue/provisão & distribução , Grupos Étnicos , Neoplasias Hematológicas/terapia , Teste de Histocompatibilidade/normas , Transfusão de Plaquetas/normas , Adolescente , Adulto , Doadores de Sangue/estatística & dados numéricos , Estudos de Coortes , Seleção do Doador/normas , Grupos Étnicos/estatística & dados numéricos , Feminino , Frequência do Gene , Antígenos HLA/sangue , Antígenos HLA/imunologia , Haplótipos , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/etnologia , Teste de Histocompatibilidade/métodos , Teste de Histocompatibilidade/estatística & dados numéricos , Humanos , Masculino , Países Baixos/epidemiologia , Transfusão de Plaquetas/métodos , Transfusão de Plaquetas/estatística & dados numéricos , Sistema de Registros , Adulto Jovem
15.
PLoS One ; 15(1): e0227670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917803

RESUMO

Torque teno virus (TTV) is an unenveloped, circular, single stranded DNA virus with a genome size of approximately 3.8 kb. Previous studies have demonstrated varying grades of association between TTV DNA levels and immune deficiencies related to age, chronic infections and cancer. Alzheimer's disease (AD) has been related to persistent viral infections such as HSV-1 and CMV, but it is not known whether TTV viral load could serve as a functional biomarker of cellular immunity in this setting. Therefore, the objective of this study was to investigate whether TTV infection and viral load is related to AD status, CMV immunity, systemic inflammation or HLA types connected to anti-viral immunity. A total of 50 AD subjects and 51 non-demented controls were included in the study. AD subjects were diagnosed according to NINCDS-ADRDA and DSM-IV criteria and neuroradiologic findings were consistent with the diagnosis. TTV viral load was analyzed in plasma samples using a quantitative real-time PCR. Using a cut-off for TTV status at 200 copies/ml, 88% (89/101) of the study subjects were classified as TTV positive. TTV viral load significantly increased with age (beta 0.049 per year, p<0.001) but significantly decreased in relation to CMV IgG levels (beta -0.022 per 1000 units, p = 0.005) and HLA-B27 positivity (beta -0.53, p = 0.023). In conclusion, TTV immune control is not significantly affected by AD status, but appears related to age, CMV humoral immune response and HLA type.


Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/virologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Infecções por Vírus de DNA/imunologia , Infecções por Vírus de DNA/virologia , Torque teno virus/patogenicidade , Carga Viral , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Estudos de Casos e Controles , Infecções por Citomegalovirus/complicações , Infecções por Vírus de DNA/complicações , Feminino , Teste de Histocompatibilidade , Humanos , Imunidade Celular , Masculino , Torque teno virus/genética , Torque teno virus/imunologia , Carga Viral/imunologia
16.
Int J Immunogenet ; 47(1): 13-23, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31903698

RESUMO

Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA-matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two-part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high-throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade/métodos , Sistema de Registros , Doadores não Relacionados , Chile , Genética Populacional , Alemanha , Antígenos HLA/genética , Antígenos HLA/imunologia , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunogenética , Índia , Polônia , Reino Unido , Estados Unidos
17.
Transfusion ; 60(3): 488-497, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31951028

RESUMO

BACKGROUND: Single antigen bead (SAB) assays are used to identify human leukocyte antigen (HLA) antibodies in patients with platelet refractoriness due to HLA Class I alloimmunization. Some laboratories use serum pretreatment regimens to eliminate interference from immunoglobulin M antibodies and complement. These modifications may contribute to interlaboratory variability, which is a recognized problem with the SAB assay. STUDY DESIGN AND METHODS: Five patients' sera were overnight shipped to 12 laboratories in the United States and internationally. Recipients used their lab's SAB procedure to identify HLA Class I antibodies. The resultant mean fluorescence intensity (MFI) data were compared by instrumentation, bead lot, and pretreatment regimens. Laboratory-specific cutoffs for positive antibodies were applied to the results. RESULTS: Interlaboratory variability for MFI values appears to be associated with different pretreatment regimens. The coefficient of variation (CV) of MFI from samples pretreated with ethylenediaminetetraacetic acid, dithiothreitol, or heat inactivation (EDHI) were similar, ranging from 14% to 56% (mean, 22%). For samples with no pretreatment, the CVs were significantly higher than EDHI-treated samples, ranging from 25% to 74% (mean, 39%; 95% confidence interval, 12.10-21.90; p < 0.0001). An intralaboratory comparison of pretreatment regimens confirmed these findings. Some positive antibody specificities present in EDHI-treated samples were negative in corresponding samples with no pretreatment when laboratory-specific cutoffs for positive antibodies were applied. CONCLUSION: Our results show that greater interlaboratory precision can be achieved when samples are pretreated with EDHI as opposed to no pretreatment, likely because these pretreatments eliminate interference from inhibitors. Inhibitors may mask antibodies, leading to missed (or uncalled) specificities when no pretreatment is used.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Isoanticorpos/imunologia , Especificidade de Anticorpos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Ditiotreitol/farmacologia , Ácido Edético/farmacologia , Feminino , Antígenos HLA/metabolismo , Teste de Histocompatibilidade , Humanos , Imunoglobulina M/metabolismo , Masculino
18.
Sci Transl Med ; 12(528)2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996467

RESUMO

Preclinical studies have shown that persistent mixed chimerism is linked to acceptance of organ allografts without immunosuppressive (IS) drugs. Mixed chimerism refers to continued mixing of donor and recipient hematopoietic cells in recipient tissues after transplantation of donor cells. To determine whether persistent mixed chimerism and tolerance can be established in patients undergoing living donor kidney transplantation, we infused allograft recipients with donor T cells and hematopoietic progenitors after posttransplant lymphoid irradiation. In 24 of 29 fully human leukocyte antigen (HLA)-matched patients who had persistent mixed chimerism for at least 6 months, complete IS drug withdrawal was achieved without subsequent evidence of rejection for at least 2 years. In 10 of 22 HLA haplotype-matched patients with persistent mixed chimerism for at least 12 months, reduction of IS drugs to tacrolimus monotherapy was achieved. Withdrawal of tacrolimus during the second year resulted in loss of detectable chimerism and subsequent rejection episodes, unless tacrolimus therapy was reinstituted. Posttransplant immune reconstitution of naïve B cells and B cell precursors was more rapid than the reconstitution of naïve T cells and thymic T cell precursors. Robust chimerism was observed only among naïve T and B cells but not among memory T cells. No evidence of rejection was observed in all surveillance graft biopsies obtained from mixed chimeric patients withdrawn from IS drugs, and none developed graft-versus-host disease. In conclusion, persistent mixed chimerism established in fully HLA- or haplotype-matched patients allowed for complete or partial IS drug withdrawal without rejection.


Assuntos
Quimerismo , Imunossupressores/farmacologia , Transplante de Rim , Suspensão de Tratamento , Adulto , Linfócitos B/imunologia , Feminino , Sobrevivência de Enxerto/imunologia , Haplótipos/genética , Teste de Histocompatibilidade , Humanos , Isoantígenos/imunologia , Teste de Cultura Mista de Linfócitos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Linfócitos T/imunologia , Tacrolimo/farmacologia , Doadores de Tecidos , Resultado do Tratamento , Adulto Jovem
19.
BMJ Open Qual ; 9(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31986117

RESUMO

The UCLA Immunogenetics Center is an Immunogenetics and Histocompatibility laboratory that performs testing for multiple transplant programmes within and outside of UCLA. The single antigen bead (SAB) test is a high complexity luminex bead test used to assess pretransplant and post-transplant patients for the presence of pathogenic human leucocyte antigen donor-specific antibody associated with allograft rejection. Efficient reporting of the SAB test has been difficult as data analysis and reports are generated in the laboratory information system (LIS) and uploaded to the electronic medical record (EMR) as PDFs. To solve this, we recently developed a state of the art reporting workflow allowing discrete reporting of SAB data (antibody specificity, mean fluorescent intensity and interpretative comments) from the LIS HistoTrac to UCLA Health System's EMR EPIC:CareConnect. However, a proportion of tests did not report to the EMR appropriately. Baseline system performance data evaluated over a 10-week period showed that ~4.5/100 tests resulted in EPIC as 'preliminary result' or 'in process' instead of 'final result' with only common cause variation. Quality improvement methods were employed to improve the process with the SMART Aim of reporting 100% of tests as 'final result'. Pareto analysis identified two errors accounting for 79% of common system-level failures-status errors and interface errors. We hypothesised that addressing the status error would reduce or eliminate the interface errors. We used the Model For Improvement to test a reprogramming intervention. Status and interface errors were completely resolved through the process improvement. Continuous monitoring revealed a system-level shift with only ~1.9/100 tests resulting inappropriately. Through the audit process, the remaining common system-level failures were identified and resolved. Therefore, 100% of tests result to EPIC as 'final result'. The study demonstrates that high complexity SAB bead data can be efficiently reported EPIC:CareConnect from HistoTrac as discrete data.


Assuntos
Especificidade de Anticorpos/imunologia , Sistemas de Informação em Laboratório Clínico/normas , Registros Eletrônicos de Saúde , Teste de Histocompatibilidade , Avaliação de Processos e Resultados em Cuidados de Saúde , Transplantes/imunologia , Registros Eletrônicos de Saúde/organização & administração , Registros Eletrônicos de Saúde/normas , Rejeição de Enxerto/imunologia , Humanos , Doadores de Tecidos , Fluxo de Trabalho
20.
Immunogenetics ; 72(1-2): 119-129, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31741009

RESUMO

Human leukocyte antigen (HLA) mismatches between donors and recipients may lead to alloreactivity after solid organ transplantation. Over the last few decades, our knowledge of the complexity of the HLA system has dramatically increased, as numerous new HLA alleles have been identified. As a result, the likelihood of alloreactive responses towards HLA mismatches after solid organ transplantation cannot easily be assessed. Algorithms are promising solutions to estimate the risk for alloreactivity after solid organ transplantation. In this review, we show that the recently developed PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes) algorithm can be used to minimize alloreactivity towards HLA mismatches. Together with the use of other algorithms and simulation approaches, the PIRCHE-II algorithm aims for a better estimated alloreactive risk for individual patients and eventually an improved graft survival after solid organ transplantation.


Assuntos
Epitopos/imunologia , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Algoritmos , Biologia Computacional/métodos , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/genética , Teste de Histocompatibilidade/métodos , Humanos , Transplante de Órgãos/métodos , Fatores de Risco , Doadores de Tecidos , Obtenção de Tecidos e Órgãos
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