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1.
Rinsho Ketsueki ; 60(9): 1324-1330, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597859

RESUMO

Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic stem cell transplantation. Therefore, the identification of an alternative donor with a lower risk of GVHD is important for patients lacking an HLA-identical sibling donor. To date, HLA studies of large cohorts of unrelated hematopoietic stem cell transplantation (UR-HSCT) have provided important and helpful information for donor selection. In UR-HSCT through Japan Marrow Donor Program, patient and donor HLA-A, -B, and -C, and HLA-DRB1 and -DQB1 double mismatches are significant risk factors for severe GVHD and mortality. HLA-DPB1 mismatch does not affect survival; however, it reduces the chances of leukemia relapse. In the analysis of a specific allele effect on transplant outcomes, HLA-C*14:02 was significantly associated with an increased risk of severe acute GVHD. The development of next-generation sequencing (NGS) has enabled full-length HLA allele typing. Evolutionary analysis of the entire HLA-DPB1 revealed that a highly conserved region from exon 3 to 3'UTR provoked acute GVHD that was different from a T-cell epitope mismatching algorithm, reflecting exon 2 polymorphisms. Furthermore, a recent study demonstrated the importance of full-length NGS HLA typing on UR-HSCT outcomes. The usage of NGS may provide important information on the implications of the HLA genes in allogeneic stem cell transplantation.


Assuntos
Doença Enxerto-Hospedeiro/genética , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Japão , Fatores de Risco , Doadores não Relacionados
2.
Lancet Haematol ; 6(11): e573-e584, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31477550

RESUMO

BACKGROUND: The introduction of donors other than HLA-matched siblings has been a pivotal change in stem cell transplantation. We aimed to assess the evolution of outcomes within donor groups over time and explore whether donor-recipient HLA disparity might be advantageous in patients with aggressive disease. METHODS: In this retrospective, multicentre study, we assessed the outcomes for adult patients (≥18 years) with haematological malignancies who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) between Jan 3, 2001, and Dec 31, 2015, and were reported to the European Society for Blood and Marrow Transplantation. The donor types studied were matched sibling, matched unrelated, mismatched unrelated, haploidentical, and cord blood donors. Unrelated non-cord-blood donors and recipients were typed at the allelic level for HLA-A, HLA-B, HLA-C, and HLA-DRB1. We evaluated trends in overall survival, non-relapse mortality, relapse incidence, progression-free survival, acute and chronic graft-versus-host disease (GVHD), and GVHD-free and relapse-free survival following transplantation from various donor types (matched sibling, matched unrelated, mismatched unrelated, haploidentical, and umbilical cord blood), and compared transplantation outcomes across three epochs (epoch 1: 2001-05; epoch 2: 2006-10; and epoch 3: 2011-15). We used Kaplan-Meier estimators for survival probabilities and cumulative incidence functions accounting for competing risks for probabilities of GHVD, relapse, and non-relapse mortality, using multiple imputations by chained equations to deal with missing data. In epoch 3, we directly compared outcomes by donor group, stratified by a novel three-level disease-risk scheme. FINDINGS: We included 106 188 patients in our analysis. The median follow-up was 4·1 years (IQR 1·7-7·7). Overall survival at 3 years increased with all donor groups between epochs 2 and 3 (matched sibling: 54·0% [95% CI 53·1-54·8] to 54·6% [53·6-55·6]; matched unrelated: 49·1% [48·0-50·2] to 51·6% [50·7-52·6]; mismatched unrelated: 37·4% [35·7-39·2] to 41·3% [39·5-43·1]; haploidentical: 34·5% [31·4-37·9] to 44·2% [42·1-46·3]; and cord blood 36·3% [33·9-39] to 43·7% [40·8-46·8]). Improvement in overall survival seems to be driven by a reduction in non-relapse mortality, except in cord blood HSCT recipients, who had a lower relapse incidence. Comparing donor groups across disease-risk strata using the novel disease-risk scheme, overall survival among recipients of matched sibling transplantations remained better than other donor groups except in high-risk disease, where overall survival with matched unrelated transplantations was not different. INTERPRETATION: Overall survival following allogeneic stem cell transplantation is improving with substantial progress among recipients of haploidentical and cord blood HSCT. Nonetheless, the traditional donor hierarchy of matched sibling donors followed by matched unrelated donors and then other donors holds. Our findings warrant further investigation and could inform decision making and the development of donor-selection algorithms. FUNDING: The Varda and Boaz Dotan Research Center in Haemato-Oncology, Tel Aviv University, and the Shalvi Foundation for Research.


Assuntos
Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doenças Hematológicas/mortalidade , Doenças Hematológicas/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Teste de Histocompatibilidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Recidiva , Sistema de Registros , Estudos Retrospectivos , Sociedades Médicas , Transplante Homólogo
3.
Lancet Haematol ; 6(11): e585-e596, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31495699

RESUMO

BACKGROUND: Donors other than matched siblings and low-intensity conditioning regimens are increasingly used in haematopoietic stem cell transplantation. We aimed to compare the relative risk of donor type and conditioning regimen intensity on the transplantation outcomes of in patients with sickle cell disease. METHODS: For this retrospective cohort study, we collected data from 90 US centres reported to the Center for International Blood and Marrow Transplant Research. Eligible patients were younger than 50 years, had genetically confirmed sickle cell disease (Hb SS) or sickle beta thalassemia (Hb Sß), and underwent allogeneic haematopoietic cell transplantation between Jan 15, 2008, and Dec 28, 2017. We considered transplants from donor-recipient pairs matched at the allele-level (HLA-A, HLA-B, HLA-C, and HLA-DRB1), including HLA-matched sibling donors, haploidentical related donors, matched unrelated donors, or mismatched unrelated donors. The main outcome was event-free survival. The effect of donor type, conditioning regimen intensity (myeloablative, non-myeloablative, and reduced-intensity regimens), age (≤12 or 13-49 years), sex, performance score, comorbidity index, recipient cytomegalovirus serostatus, graft type (bone marrow, peripheral blood, or umbilical cord blood), and transplantation period (2008-12 and 2013-17) on outcomes was studied using Cox regression models. FINDINGS: Of 996 patients with sickle cell disease and who underwent transplantation in 2008-17, 910 (91%) were included (558 [61%] patients had HLA-matched sibling donors, 137 [15%] haploidentical related donors, 111 [12%] matched unrelated donors, and 104 [11%] mismatched unrelated donors). The median follow-up was 36 months (IQR 18-60) after transplantation from HLA-matched siblings, 25 months (12-48) after transplantation from haploidentical related donors, 37 months (23-60) after transplantation from HLA-matched unrelated donors, and 47 months (24-72) after transplantation from mismatched unrelated donors. Event-free survival was worse in recipients aged 13 years or older than in those younger than 13 years (hazard ratio 1·74, 95% CI 1·24-2·45; p=0·0014) and in those who received a transplant from haploidentical related donors (5·30, 3·17-8·86; p<0·0001), matched unrelated donors (3·71, 2·39-5·75; p<0·0001), and mismatched unrelated donors (4·34, 2·58-7·32; p<0·0001) than in patients who received a transplant from matched siblings. There was no significant difference in event-free survival between recipients of transplants from non-sibling donors: haploidentical related donors (1·43, 0·81-2·50; p=0·21) or mismatched unrelated donors (1·17, 0·67-2·05; p=0·58) versus HLA-matched unrelated donors, or mismatched unrelated donors versus haploidentical related donors (1·22, 0·65-2·27; p=0·98). Event-free survival was also worse in patients conditioned with reduced-intensity regimens (1·97, 1·15-3·36; p=0·013) than in those conditioned with non-myeloablative regimens, but did not differ between those who received myeloablative compared with non-myeloablative regimens (1·57, 0·95-2·61; p=0·079). Interpretation Our data suggest that event-free survival is improved in patients with sickle cell disease who receive an allogenic transplantation at age 12 years or younger and those with an HLA-matched sibling donor. For patients without a matched sibling available for transplantation, our data do not favour one alternative donor type over another in this setting. FUNDING: National Institutes of Health and US Health Services Research Administration, Department of Health and Human Services.


Assuntos
Anemia Falciforme/terapia , Transplante de Medula Óssea , Sangue Fetal/transplante , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Anemia Falciforme/mortalidade , Anemia Falciforme/patologia , Doadores de Sangue , Transplante de Medula Óssea/efeitos adversos , Criança , Feminino , Doença Enxerto-Hospedeiro/etiologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto Jovem
4.
Transplant Proc ; 51(6): 1796-1800, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399165

RESUMO

BACKGROUND: In kidney transplantation, donor recipient human leukocyte antigen (HLA)-DR mismatch signals high immunologic risk and portends inferior outcomes. We compared the impacts of depleting vs non-depleting antibody induction on the outcomes in kidney transplant recipients (KTRs) at different levels of HLA-DR mismatches. METHODS: Using the Organ Procurement and Transplantation Network/United Network for Organ Sharing database, we identified adult KTRs from 2001 to 2015 who received induction therapy with either depleting (thymoglobulin/alemtuzumab) or non-depleting (basiliximab/daclizumab) antibody and were discharged on calcineurin inhibitor/mycophenolic acid maintenance. Patients were then stratified by the number of donor-recipient HLA-DR mismatches (0, 1, 2) in both living donor (LD) and deceased donor (DD) KTRs. Under each HLA-DR mismatch category, long-term outcomes were compared for depleting vs non-depleting induction using a Cox model. RESULTS: A total of 63,821 LD (HLA-DR mismatches: 0, n = 6945 [depleting = 4409, non-depleting = 2536]; 1, n = 19,557 [depleting = 13,558, non-depleting = 6019]; and 2, n = 10,727 [depleting = 7694, non-depleting = 3033]) and 64,922 DD (HLA-DR mismatches: 0, n = 13,915 [depleting = 10,124, non-depleting = 3791]; 1, n = 27,994 [depleting = 20,454, non-depleting = 7540]; and 2, n = 23,013 [depleting = 16,908, non-depleting = 6105]) KTRs were included in the analysis. Adjusted patient death risk was significantly lower in the depleting vs non-depleting antibody induction group among DD kidney recipients (hazard ratio 0.90, 95% CI 0.85-0.96, P = .001) and trended lower among LD kidney recipients (HR 0.88, 95% 0.79-1.01, P = .05) with 2 HLA-DR mismatches. DISCUSSION: Our study found a patient survival benefit associated with the use of perioperative induction with depleting when compared to non-depleting antibody in KTRs with 2 HLA-DR mismatches and maintained on a calcineurin inhibitor/mycophenolic acid regimen.


Assuntos
Incompatibilidade de Grupos Sanguíneos/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA-DR/imunologia , Imunossupressão/métodos , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Adulto , Alemtuzumab/uso terapêutico , Anticorpos/imunologia , Soro Antilinfocitário/imunologia , Soro Antilinfocitário/uso terapêutico , Basiliximab/imunologia , Basiliximab/uso terapêutico , Inibidores de Calcineurina/imunologia , Inibidores de Calcineurina/uso terapêutico , Contraindicações de Procedimentos , Daclizumabe/imunologia , Daclizumabe/uso terapêutico , Bases de Dados Factuais , Feminino , Teste de Histocompatibilidade , Humanos , Rim/imunologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/imunologia , Ácido Micofenólico/uso terapêutico , Modelos de Riscos Proporcionais , Resultado do Tratamento
5.
Transplant Proc ; 51(6): 1982-1989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399180

RESUMO

OBJECTIVE: Human leukocyte antigen match is the most important donor factor affecting transplant outcome. The HLA-DPB1 mismatch on the clinical outcome of hematopoietic stem cell transplant (HSCT) is less clear. This study is the first meta-analysis to investigate the impact of HLA-DPB1 loci mismatch on clinical outcome after unrelated donor HSCT for hematologic malignant disease. METHODS: We electronically searched the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and a related database (January 1995-December 2018) for all relevant articles. Comparative studies were carried out to investigate the impact of HLA-DPB1 loci mismatch on clinical outcome after unrelated donor HSCT, that is, the disease-free survival, engraftment, graft-vs-host disease, relapse, and transplant-related mortality (TRM). We performed a meta-analysis using Review Manager 5.3.5 software and adopted funnel plot regression to assess the publication bias. RESULTS: A total of 1570 articles were retrieved; 21 studies including 27,852 patients were assessed. Pooled comparisons of studies found that the HLA-DPB1-mismatched group had a lower rate of disease-free survival than the DPB1-matched group and lower overall survival in non-T cell-depleted transplant than the DPB1-matched group. The DPB1-mismatched group has higher incidence of acute graft-vs-host disease (aGVHD) and severe (≥ III degree) aGVHD, lower relapse rate, and higher TRM. Moreover, compared with 1-antigen mismatch, 2-antigen mismatch in DPB1 had a higher risk of TRM and a lower relapse rate, and the nonpermissive DPB1 mismatch had significantly higher rate of severe aGvHD and lower rate of disease relapse. CONCLUSIONS: This analysis confirmed that HLA-DPB1 has important influence on survival and transplant-related complications during unrelated donor HSCT, and HLA-DPB1 donor selection strategies have been proposed based on personalized algorithm.


Assuntos
Incompatibilidade de Grupos Sanguíneos/mortalidade , Cadeias beta de HLA-DP/imunologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Adulto , Incompatibilidade de Grupos Sanguíneos/imunologia , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Doadores não Relacionados
6.
Rinsho Ketsueki ; 60(6): 620-625, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281154

RESUMO

Since the introduction of hematopoietic stem cell transplantation (HSCT), matching the HLA with the donor and recipient is the most important factor in improving the outcome. Currently, we are getting familiar with cord blood transplantation and haplo-identical stem cell transplantation which are beyond HLA disparity. However, even in this era, the significance of HLA for HSCT has not changed, and new technology provides knowledge regarding HLA and HSCT. Usually, HLA typing methods only estimate the allele, but next generation sequencing (NGS) can detect the whole sequence of the HLA gene. Moreover, because the NGS method can be used for quantitative analysis, we can also detect 6pLOH in some disease conditions. Furthermore, a previous report showed that HLA epitope mismatch also influenced the outcome of HSCT. This review shows this new technology and findings on HLA and HSCT.


Assuntos
Genômica/tendências , Antígenos HLA/genética , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Transplante de Células-Tronco Hematopoéticas , Humanos
7.
Transplant Proc ; 51(5): 1575-1578, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31155195

RESUMO

BACKGROUND: Superior patient and graft survival rates have been attributed to living donor kidney transplant (LDKT) when compared to deceased donor transplantation. The aim of this study was to assess graft survival in a population of LDKT in the last 14 years and the potential impact of some clinical features. METHODS: A retrospective observational study was conducted, reviewing the records of all patients undergoing LDKT in one center from January 1, 2004, to December 31, 2017. Survival data were evaluated by Kaplan-Meier, log rank test, and Cox regression. RESULTS: Two hundred seventy-seven LDKT were performed. The median follow-up time was 4 (0-13) years. Graft loss was observed in 9% of patients; 4 patients died. The overall survival was 97% at year 1, 94% at year 5, and 83% at years 10 and 13. We found a significantly worse graft survival in patients with early vascular complications that required surgical intervention (P = .00) ≥3 HLA MM (P = .01), ≥1 HLA-DR MM (P = .04) and female recipients (P = .01). The negative impact of ≥1 HLA-B MM on survival was borderline (P = .05). After excluding early graft losses secondary to vascular events, ≥1 HLA-A MM and rejection have also implicated a negative impact on survival (P = .04 and .01, respectively). In the multivariate analysis, these variables were still related to inferior survival. CONCLUSIONS: We observed a good overall graft survival (>80% after 13 years). Possible factors related to poor outcomes suggested by this study were early vascular complications; HLA mismatches; rejection; and, with less certainty, female recipients.


Assuntos
Sobrevivência de Enxerto/fisiologia , Transplante de Rim/mortalidade , Doadores Vivos , Adulto , Feminino , Rejeição de Enxerto/epidemiologia , Antígenos HLA-DR , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo
8.
Genet Test Mol Biomarkers ; 23(6): 418-422, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31066583

RESUMO

Aim: Celiac disease (CD) is strongly associated with HLA-DQ2.2, HLA-DQ2.5, and HLA-DQ8. Up to 99.7% of all CD patients are positive for either one or two of these genetic markers, demonstrating a high negative predictive value. This has led to the development of diagnostic kits that, instead of providing a full HLA-DQ typing, detect only these three HLA-DQ types. Our aim was to compare three different kits for their performance, utilization, and costs. Because 0.4-3.6% of all CD patients test positive for HLA-DQ7 and negative for the aforementioned types, information provided by the kits regarding DQ7 alpha and beta chains was evaluated as well. Materials and Methods: Fifty DNA samples previously typed with the SSCP method were analyzed using three commercial kits. Results and Discussion: All kits report hetero- or homozygosity for HLA-DQ2.5. The XeliGen kit directly detects HLA-DQ7, but is relatively expensive. The MLPA kit is the least expensive in terms of reagents and may indirectly detect HLA-DQ7. The CeliaSCAN kit is easy to use and provides indirect information about HLA-DQ7.5. Conclusion: All kits correctly identify the CD risk genes. The resources of the laboratory and the intended use should determine the preference for any of the HLA-DQ typing kits herein described.


Assuntos
Doença Celíaca/diagnóstico , Antígenos HLA-DQ/genética , Teste de Histocompatibilidade/métodos , Alelos , Doença Celíaca/genética , Feminino , Frequência do Gene/genética , Marcadores Genéticos , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Genótipo , Humanos , Masculino , Kit de Reagentes para Diagnóstico , Fatores de Risco
9.
Transplant Proc ; 51(4): 1021-1023, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31101163

RESUMO

Cytotoxic flow cytometric crossmatch (cFCXM), identified by detecting complement-mediated cytotoxic cell death in addition to the capability of showing the alloantibodies binding onto lymphocytes at the same time, can reduce the necessary time and workload in evaluating alloantibodies. More data from clinical samples are needed for cFCXM to be accepted by tissue typing laboratories. In this study, we compared cFCXM with complement-dependent lymphocytotoxicity and standard flow cytometric crossmatch in 41 renal pretransplant patients. A comparison of the obtained data was performed using Spearman's correlation test. We found that cFCXM showed no statistically significant differences with complement-dependent lymphocytotoxicity and flow cytometric crossmatch. We believe that cFCXM can be used in clinical laboratories in the near future following intra-laboratory validation.


Assuntos
Testes Imunológicos de Citotoxicidade/métodos , Citometria de Fluxo/métodos , Teste de Histocompatibilidade/métodos , Transplante de Rim , Feminino , Humanos , Isoanticorpos/análise , Isoanticorpos/imunologia , Masculino
10.
N Engl J Med ; 380(20): 1918-1928, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31091373

RESUMO

BACKGROUND: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection. METHODS: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses. RESULTS: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses. CONCLUSIONS: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Variações do Número de Cópias de DNA , Rejeição de Enxerto/genética , Transplante de Rim , Proteínas com Domínio LIM/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Estudos de Coortes , Estudos de Associação Genética , Genótipo , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , Imunoglobulina G/sangue , Proteínas com Domínio LIM/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos
12.
Transplant Proc ; 51(3): 707-714, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979454

RESUMO

Single-antigen bead (SAB) platform permits the identification of antibodies not detectable by complement-dependent lymphocytotoxicity test, but their clinical significance is not completely understood. The aim of this study was to evaluate whether the presence of pretransplant SAB-detected antibodies is associated with the development of allograft failure. This is a single-center cohort study with 10-year follow-up in which 573 kidney recipients with negative pretransplant complement-dependent lymphocytotoxicity crossmatch who received transplants at the Kidney Transplant Center of Policlinico, Milan, from deceased donors between 1996 and 2005 were evaluated. Pretransplant plasma samples were retrospectively analyzed by SAB assay. Survival analyses were performed to assess the risk of allograft failures by SAB-detected antibodies. Pretransplant antibodies were found in 160 (28.0%) recipients, of whom 42 subsequently developed an allograft failure for a survival rate of 70.9% (95% confidence interval [CI), 63.5-78.4). Among those without antibodies, 58 (14.0%) returned to dialysis with a survival rate of 84.7% (95% CI, 81.0-88.4). In Cox regression analyses, patients with SAB-positivity had 2-fold higher risk of allograft failure than those who were SAB-negative (hazard ratio, 2.07; 95% CI, 1.39-2.79). Results did not change after adjustment for putative confounders. In conclusion, in this single-center cohort, 10-year allograft survival rate was significantly influenced by the presence of SAB-detected antibodies.


Assuntos
Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Teste de Histocompatibilidade/métodos , Isoanticorpos/imunologia , Transplante de Rim/métodos , Adulto , Estudos de Coortes , Feminino , Rejeição de Enxerto/imunologia , Humanos , Isoanticorpos/análise , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos
13.
Yi Chuan ; 41(4): 337-348, 2019 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-30992255

RESUMO

The high-resolution and accurate typing of human leukocyte antigen (HLA) is of great significance for the study of tissue matching in organ transplantation and the correlation between HLA and disease. In this study, the peripheral blood of 12 patients with primary hepatocellular carcinoma was used to compare the advantages and disadvantages of the next- and third-generation sequencing technology for high-resolution HLA typing. In addition, probe capture technology was used to capture the MHC region of YH and HeLa standard cell lines, and a primary hepatocellular carcinoma patient. The captured products were sequenced using PacBio platform to assess the potential of ultra-long reads sequencing technology for analysis of the entire MHC region. Our results showed that: (1) the next- and third-generation sequencing technology can both achieve 6-8 digit high resolution in HLA typing. However, the coverage of the third-generation is significantly better than the next-generation sequencing technology. (2) The ultra-long reads of the third generation sequencing can directly span the entire amplicon region, which has obvious advantages for haplotype phasing, with 92.79% of the HLA genes having accurate phasing results, which is much higher than the 75.65% from the next-generation data. (3) The long-reads from the third generating sequencing can not only be used to assemble the MHC region but also the ability to phase the entire MHC region of 3.6 Mb, thereby helping to clarify the localization information of the mutation sites, alleles and non-coding regions on each MHC haplotype, and providing a theoretical basis for the study of immune and other related diseases.


Assuntos
Antígenos HLA/genética , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Alelos , Carcinoma Hepatocelular/genética , Células HeLa , Humanos , Neoplasias Hepáticas/genética , Análise de Sequência de DNA
14.
PLoS One ; 14(3): e0213179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845238

RESUMO

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of pulmonary surfactant in alveolar macrophages and alveoli, resulting in respiratory impairment and an increased risk of opportunistic infections. Autoimmune PAP is an autoimmune lung disease that is caused by autoantibodies directed against granulocyte-macrophage colony-stimulating factor (GM-CSF). A shared feature among many autoimmune diseases is a distinct genetic association to HLA alleles. In the present study, we HLA-typed patients with autoimmune PAP to determine if this disease had any HLA association. We analyzed amino acid and allele associations for HLA-A, B, C, DRB1, DQB1, DPB1, DRB3, DRB4 and DRB5 in 41 autoimmune PAP patients compared to 1000 ethnic-matched controls and did not find any HLA association with autoimmune PAP. Collectively, these data may suggest the absence of a genetic association to the HLA in the development of autoimmune PAP.


Assuntos
Doenças Autoimunes/patologia , Antígenos HLA/genética , Proteinose Alveolar Pulmonar/patologia , Adulto , Alelos , Autoanticorpos/sangue , Doenças Autoimunes/genética , Feminino , Frequência do Gene , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteinose Alveolar Pulmonar/genética
15.
Transplant Proc ; 51(2): 497-503, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30879576

RESUMO

The impact of solid-phase immunoassay for HLA antibody detection on the field of transplantation has been extremely significant by providing the most sensitive and precise method for characterization of HLA antibodies. However, despite all the benefits, technical limitations and inherent artifacts represent significant challenges, particularly with Luminex-based single-antigen bead (SAB) assay. Discordant results between antibody detection (screening assay) and identification (SAB) is not uncommon. Positive SAB assay in the context of negative screening testing is well documented and attributed to altered tertiary structure of HLA molecules exposing new epitopes or detection of naturally occurring antibodies. However, there are few reports that addressed the opposite scenario when negative SAB appeared in the context of positive screening assay. In such discrepant results, unmissed HLA antibody has to be excluded with certainty by other tests; however, with the availability of variable assays it may be difficult to choose the best combinations that clarify discrepancy without adding more confusion. Here we describe the results of correlation between 2 antibody screening solid-phase immunoassays (LABScreen Mixed using Luminex and FlowPRA Screen) on conventional flow cytometry and compare their outcomes with SAB and crossmatch results.


Assuntos
Citometria de Fluxo , Antígenos HLA/imunologia , Teste de Histocompatibilidade/métodos , Imunoensaio , Isoanticorpos/análise , Transplante de Rim , Humanos
16.
Zhonghua Yi Xue Za Zhi ; 99(12): 901-906, 2019 Mar 26.
Artigo em Chinês | MEDLINE | ID: mdl-30917438

RESUMO

Objective: To analyze the distribution frequency of HLA antigen gene and antibody, and explore the relationship of PIRCHE score with DSA production and AMR occurrence. Methods: Kidney transplantation cases of department Kidney transplantation, the First Hospital of Xi'an Jiaotong University from November 2013 to June 2017 were included in our study. HLA high resolution typing were detected with LAB Type (TM) SSO method. HLA classⅠ & Ⅱ antibody detection were tested by LAB screen Single Antigen beads with Luminex 200 technology. PIRCHE score were graded with PIRCHE score system. Results: HLA high resolution classification data of 798 recipients and 409 donors showed that HLA A2, A11, A24 were common in HLA A locus; HLA B46, B51 B60, B35, B62, B61 were common in HLA B locus; HLA DR9, DR4, DR15, DR12, DR7, DR11 were common in HLA DR locus; HLA DQ7, DQ6, DQ5, DQ9, DQ2 were common in HLA DQ locus. The positive cases of HLA class Ⅰ & Ⅱ antibody and DSA were 105, 40 and 32, respectively. The most common of HLA class Ⅰ antibody were A24 and B7 antibody; the most common of HLA class Ⅱ antibody was DQ antibody, including DQ2, DQ9, DQ4, DQ6, DQ7 and DQ8. PIRCHE scores of living donor transplantation recipients were significantly lower than DCD group (P<0.01). PIRCHE score of DSA(+) and DSA(+)AMR(+) group were markedly higher than that of DSA(-)and DSA(+)AMR(-)group, respectively(P<0.05); analysis of ROC curve on PIRCHE scores could predict DSA production and AMR occurrence. The AUC for prediction DSA production was 0.80, and the critical value was 115.5. For prediction of AMR, the AUC was 0.89 and the critical value was 133.5. Conclusions: The common HLA antigens have stronger immunogenicity, and easy to stimulate the body to produce HLA antibodies; matching of common antigen sites and HLA class Ⅱ antigen should be attached importance before kidney transplantation. PIRCHE score can predict the generation of DSA and the occurrence of AMR effectively. PIRCHE score for HLA match, is more sensitive than traditional methods, and contains more information.


Assuntos
Antígenos HLA/imunologia , Anticorpos , Rejeição de Enxerto , Teste de Histocompatibilidade , Isoanticorpos , Transplante de Rim , Doadores de Tecidos
18.
BMC Cancer ; 19(1): 242, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885156

RESUMO

BACKGROUND: Patients with relapsed/refractory acute myeloid leukemia after hematopoietic stem cell transplantation (HSCT) have a poor prognosis, with a 2-year survival rate of 14%. The optimal treatment for these patients remains unclear. To treat these patients, we designed a new salvage regimen consisting of decitabine, cladribine, cytarabine, and granulocyte-stimulating factor (D-CLAG). CASE PRESENTATION: Here, we describe a case of acute monocytic leukemia with a complex karyotype in a 38-year-old female patient who relapsed after her first HSCT, which was performed using a matched sibling donor. The patient did not respond to standard induction chemotherapy and subsequently achieved complete remission with the D-CLAG regimen. No severe hematological or extramedullary toxicity was observed. Subsequently, the patient received a second D-CLAG regimen as a bridge therapy and directly underwent haploidentical related HSCT. Following HSCT, the marrow showed complete hematologic and cytogenetic remission. Currently, 1 year after transplantation, the patient's general condition remains good. CONCLUSIONS: This case suggests that the D-CLAG regimen can be an option for reinduction in relapsed refractory AML patients as a bridge to transplantation. Nevertheless, further research will be required in the future as this report describes only a single case.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Decitabina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia/terapia , Adulto , Cladribina/uso terapêutico , Citarabina/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Antígenos HLA/imunologia , Teste de Histocompatibilidade , Humanos , Indução de Remissão/métodos , Terapia de Salvação/métodos , Irmãos , Transplante Haploidêntico/métodos , Resultado do Tratamento
19.
Exp Clin Transplant ; 17(Suppl 1): 6-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777518

RESUMO

OBJECTIVES: To identify the risk of developing acute rejection, allograft fibrosis, and antibody-mediated rejection, a retrospective review of pediatric patients who underwent liver transplant between July 31, 1998 and February 29, 2016 and had donor-specific antibodies measured at time of liver biopsy was undertaken. MATERIALS AND METHODS: HLAMatchmaker Software (http://www.hlamatchmaker.net) was used to define epitope mismatches between donors and recipients and to predict de novo donor-specific antibody risk. Epitope mismatches were evaluated for their immunogenicity. RESULTS: In our group of 42 recipients, 20 (48%) had donor-specific antibodies. Having an antibody against HLA-DQB1*02 was associated with acute rejection (66.6% vs 36%; P = .024). We found that DQ epitope mismatch load was greater in recipients with class II donor-specific antibodies (9.7 vs 3.6; P = .001). HLA-DQ (7.4 vs 3.6; P = .04) and HLA-DR (8.8 vs 3.8; P = .04) epitope mismatch loads were higher in recipients with DQ + DR donor-specific antibodies. A high portal fibrosis score was associated with higher mismatch load at the DQ locus (P = .005) and DQ + DR loci (P = .03). Having > 5 or > 6 epitope mismatch loads at the DQ locus identified a threshold above which development of DQ donor-specific antibodies would occur (area under the curve = 0.878). Mismatches for eplet 4Q, 45GE, 52PQ, and 52PL, thought to be immunodominant epitopes, were observed for several recipients. CONCLUSIONS: Knowledge of epitope mismatches between recipients and donors may aid transplant physicians in devising immunosuppression strategies.


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Antígenos HLA/imunologia , Histocompatibilidade , Isoanticorpos/imunologia , Transplante de Fígado/efeitos adversos , Adolescente , Fatores Etários , Criança , Pré-Escolar , Connecticut , Feminino , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Teste de Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
20.
Exp Clin Transplant ; 17(Suppl 1): 38-42, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777521

RESUMO

Recent developments have been achieved for better matching in solid-organ transplantation by epitope matching. HLA matching remains a standard immunologic strategy to determine organ compatibility for recipients. Advancements in tissue typing have introduced HLA matching at the epitope level. For this, B cells are able to recognize polymorphic amino acid configurations, which are named epitopes. However, antibody production against these epitopes may be a leading cause of rejection. Although data to support the added clinical benefit of epitope matching over traditional antigen matching are still lacking, there are at least 2 theoretical reasons for epitope matching: (1) to avoid future allosensitization with the development of anti-HLA antibodies and (2) to allow selection of a suitable allograft for highly sensitized patients through virtual crossmatch. Sensitive antibody tests with a comprehensive panel of single alleles have yielded informative, donor-specific antibody reactivity patterns that can be analyzed with a computer algorithm. This program (HLAMatchmaker) uses structurally defined eplets to describe epitopes that can react with specific antibodies. Although low mean fluorescence intensity levels by Luminex (Austin, TX, USA) assay are usually considered low risk for solid organ transplant, it could be important in posttransplant humoral rejection. Thus, specific shared eplets should always be investigated with respect to previous transplant mismatches. Epitopes are present on a single HLA (private epitope) or shared by multiple antigens (public epitope). The phenomenon of crossreactivity in HLA testing, often explained as crossreactive groups of antigens with antibody, can be clearly explained now by public epitopes, an antibody targeting an epitope that shows positive reaction with all antigens sharing the epitope. A better understanding of the immunogenicity and structural characteristics of HLA epitopes will guide us to consider epitope matching as an important parameter for donor selection in kidney transplant in the near future.


Assuntos
Mapeamento de Epitopos/métodos , Epitopos/imunologia , Antígenos HLA/imunologia , Teste de Histocompatibilidade/métodos , Histocompatibilidade , Isoanticorpos/imunologia , Transplante de Rim/métodos , Animais , Tomada de Decisão Clínica , Seleção do Doador , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Valor Preditivo dos Testes , Fatores de Risco , Resultado do Tratamento
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