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2.
Ann Hematol ; 98(6): 1485-1493, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30915500

RESUMO

Post-transplantation cyclophosphamide (PTCy) demonstrated effectiveness to prevent GVHD after haploidentical hematopoietic cell transplantation (HCT). Reducing toxicities with a maximized efficacy is still challenging in HCT. In this retrospective study, we analyzed the safety and efficacy of transplantation from a 1-antigen HLA-mismatched unrelated donor (9/10 MMUD) in 80 patients with hematological disorders between 2010 and 2018; 22 patients received PTCy with a reduced dose of 40 mg/kg, cyclosporine A, and mycophenolate mofetil (MMF); 58 patients received anti-thymocyte globulin (ATG), cyclosporine A, and either methotrexate or MMF for GVHD prophylaxis. Cumulative incidence (CI) of acute GVHD grades II-IV in the PTCy group was significantly lower (15% vs. 50%, p = 0.006); however, CI of chronic GVHD was (not significantly) lower in the PTCy group (26% vs. 35%, p = 0.137). One-year OS was significantly longer (p = 0.008) in the PTCy group with a similar 1-year PFS (p = 0.114) in both groups. Rates of 1-year relapse and non-relapse mortality were similar. Median time to neutrophil engraftment was comparable in both GVHD prophylaxis groups (14 days vs. 16 days, respectively, p = 0.107). Our results show that a lower dose of PTCy-based prophylaxis is an effective and safe strategy to prevent acute GVHD in HCT with 9/10 MMUD compared to ATG.


Assuntos
Soro Antilinfocitário/uso terapêutico , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Adulto , Idoso , Anemia Aplástica/terapia , Doenças da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea , Ciclofosfamida/administração & dosagem , Ciclosporina/uso terapêutico , Avaliação de Medicamentos , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/análise , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemoglobinúria Paroxística/terapia , Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Neoplasias/terapia , Estudos Retrospectivos , Linfócitos T/imunologia , Doadores de Tecidos
4.
Ann Hematol ; 98(3): 753-762, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30617644

RESUMO

In acute myeloid leukemia (AML), primary refractory or relapsed disease, secondary AML, and leukemia with unfavorable genetics are considered high-risk AML (hrAML), with allogeneic stem cell transplantation (SCT) representing the standard treatment. Sequential conditioning has been successfully used for SCT in hrAML in HLA-matched transplants, and found its way into HLA-haploidentical SCT (haplo-SCT) later on. Hence, sequential conditioning had become standard for all patients with hrAML in our two centers, regardless of donor type. Thereby, HLA-matched family or unrelated transplants were first/second choice, post-transplant cyclophosphamide (PTCY)-based haplo-SCT was chosen in patients missing matched donors or requiring urgent transplantation. To compare the outcome after HLA-matched and haplo-SCT for hrAML following sequential conditioning, we performed a retrospective, matched-pair comparison, using disease stage, genetic subgroups and age as matching criteria. Thirty-four well-matched pairs were identified. At SCT, patients (median age 54 years) were untreated (9%), had remission (13%), or active disease (78%). Three-year overall and leukemia-free survival (OS/LFS) of the entire cohort was 56 ± 7%/49 ± 7%, without significant differences between donor types (OS after HLA-matched/haplo-SCT 62 ± 10%/52 ± 9% (p = 0.21), LFS 53 ± 10%/46 ± 9% (p = 0.26)). Similarly, the cumulative incidence of relapse, non-relapse-mortality and chronic GvHD, as well as GvHD-free, relapse-free survival (GRFS), and chronic GvHD-free, relapse-free survival (cGRFS), were comparable. However, a higher incidence of acute GvHD ≥ II° was observed after HLA-matched SCT (15 ± 1% versus 50 ± 2%, p = 0.001). In conclusion, sequential conditioning SCT achieved remarkable results in hrAML, independently from donor type. PTCY-based haplo-SCT produced results that were comparable to HLA-matched SCT and can be used as an alternative option.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Aloenxertos , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/análise , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Teste de Histocompatibilidade , Humanos , Incidência , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Doadores não Relacionados
5.
Acta Biomed ; 89(9-S): 17-21, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30561391

RESUMO

Celiac disease is a chronic immune-mediated enteropathy triggered by exposure to dietary gluten in genetically predisposed individuals. Many genes involved in the pathogenesis have been identified and a crucial role is known to be played by the Human Leukocyte Antigen (HLA) system. The main determinants for genetic susceptibility are HLA-DQA1 and HLA-DQB1 genes encoding for HLA-DQ2 and HLA-DQ8 molecules, carried by almost all patients affected. However, since HLA-DQ2 and HLA-DQ8 heterodimers explain almost 40% of the disease heritability, HLA typing should not be applied in diagnosis, but exclusively to clarify uncertain diagnoses, considering its negative predictive value.


Assuntos
Doença Celíaca/genética , Antígenos HLA/genética , Doença Celíaca/imunologia , Dimerização , Predisposição Genética para Doença , Genótipo , Antígenos HLA/análise , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Humanos , Valor Preditivo dos Testes
6.
Mol Biol Rep ; 45(6): 2821-2829, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30229475

RESUMO

The Public Cord Blood Bank of Jeevan Stem Cell Foundation was established in 2008 to harvest cord blood units and make them available to treat multiple blood disorders through Hematopoietic Stem Cell Transplants. We studied Human Leucocyte Antigen (HLA)-A, -B, -C, -DRB1 and -DQB1 allele and haplotype diversity in a sample of 2491 unrelated cord-blood units from Jeevan's Public Cord Blood Bank (part of Be The Cure Registry) in the Tamil Nadu state in the Indian Peninsula.


Assuntos
Antígenos HLA/genética , Alelos , Feminino , Sangue Fetal/citologia , Sangue Fetal/fisiologia , Frequência do Gene/genética , Genótipo , Antígenos HLA/análise , Haplótipos , Antígenos de Histocompatibilidade Classe I , Humanos , Índia , Recém-Nascido , Masculino
7.
Am J Hematol ; 93(10): 1236-1244, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30058714

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most powerful therapy preventing relapse in patients with adverse cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1). In the absence of a matched related donor, potential alternatives include 10/10, 9/10 HLA-matched unrelated (UD) or haploidentical (Haplo) donors. We analyzed clinical outcomes of patients undergoing T-cell repleted Haplo (n = 74), 10/10 UD (n = 433) and 9/10 UD HSCT (n = 123) from 2007 to 2015, reported to the EBMT Registry. Adverse risk AML was defined according to the 2017 ELN cytogenetic risk classification. The 2-year nonrelapse mortality was 19% for Haplo, 18% for 10/10 UD and 18% for 9/10 UD (P = .9). The relapse incidence was not significantly affected by donor source, with a 2-year incidence of 27% for Haplo HSCT, 39% for 10/10 UD and 37% for 9/10 UD SCT (P = .3). We show comparable probabilities of leukemia-free survival (LFS) and overall survival (OS) at 2 years among Haplo HSCT, 10/10 UD SCT and 9/10 UD SCT (53% and 59%, 43% and 50%, 44% and 50%, respectively, P = .5 for both parameters). The type of donor was not significantly associated with either acute or chronic graft-vs.-host disease incidence. Using multivariable Cox model, Haplo HSCT recipients experienced comparable OS and LFS to 10/10 and 9/10 UD. In the present series of adverse cytogenetics AML patients in CR1, Haplo HSCT recipients had comparable outcomes to those of 10/10 and 9/10 UDs, suggesting that all these types of HSCT may be considered a valid option in this high risk population.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Doadores não Relacionados , Cariótipo Anormal , Adolescente , Adulto , Idoso , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/análise , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
8.
Int J Lab Hematol ; 40 Suppl 1: 74-82, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29741247

RESUMO

The hemoglobinopathies, as a group, are one of the most common serious monogenic diseases in the world. An accepted and widely adopted approach to reduce the number of new cases involves carrier-screening programs, with the option of prenatal diagnosis (PND) or preimplantation diagnosis (preimplantation genetic testing for monogenic disease, PGT-M) for carrier couples. The aim of PND is to provide an accurate result as early in pregnancy as possible, which necessitates prior identification of the parental disease-causing mutations, as well as safe and timely biopsy of fetal material. PGT-M aims to characterize the genetic status of in vitro fertilized embryos during assisted reproductive technology (ART), in a few cells biopsied from oocytes/zygotes or embryos, in order to initiate an unaffected pregnancy. Another application of PGT-M is preimplantation genetic diagnosis for human leukocyte antigen (PGD-HLA), which, in addition to identifying unaffected embryos, also characterizes the embryos that are HLA compatible with an existing affected child requiring a hemopoietic stem cell transplantation (HSCT). This review outlines the current practices related to these procedures, with emphasis on the aspects related to laboratory techniques. Finally, future prospects related to developments in noninvasive prenatal diagnosis are discussed.


Assuntos
Hemoglobinopatias/diagnóstico , Diagnóstico Pré-Implantação/métodos , Diagnóstico Pré-Natal/métodos , Técnicas de Laboratório Clínico , Feminino , Testes Genéticos/métodos , Antígenos HLA/análise , Humanos , Gravidez
9.
Sci Rep ; 8(1): 5014, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29568084

RESUMO

Mesenchymal stem/stromal cells (MSCs) derived from placental tissue show great therapeutic potential and have been used in medical treatment, but the similarity and differences between the MSCs derived from various parts of the placenta remain unclear. In this study, we compared MSCs derived from different perinatal tissues, including the umbilical cord (UC), amniotic membrane (AM), chorionic plate (CP) and decidua parietalis (DP). Using human leukocyte antigen (HLA) typing and karyotype analysis, we found that the first three cell types were derived from the foetus, while the MSCs from the decidua parietalis were derived from the maternal portion of the placental tissue. Our results indicate that both foetal and maternal MSCs share a similar phenotype and multi-lineage differentiation potential, but foetal MSCs show a significantly higher expansion capacity than do maternal MSCs. Furthermore, MSCs from all sources showed significant differences in the levels of several paracrine factors.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Placenta/citologia , Cordão Umbilical/citologia , Biomarcadores/análise , Biomarcadores/metabolismo , Diferenciação Celular/fisiologia , Separação Celular/métodos , Células Cultivadas , Feminino , Feto/citologia , Citometria de Fluxo/métodos , Antígenos HLA/análise , Humanos , Imunofenotipagem/métodos , Cariotipagem , Gravidez , Cultura Primária de Células , Molécula 1 de Adesão de Célula Vascular/análise , Molécula 1 de Adesão de Célula Vascular/metabolismo
10.
Proteomics ; 18(12): e1700410, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29493099

RESUMO

Immunopeptidomes promise novel surface markers as ideal immunotherapy targets, but their characterization by mass spectrometry (MS) remains challenging. Until recently, cell numbers exceeding 109 were needed to survey thousands of HLA ligands. Such limited analytical sensitivity has historically constrained the types of clinical specimens that can be evaluated to cell cultures or bulk tissues. Measuring immunopeptidomes from purified cell subpopulations would be preferable for many applications, particularly those evaluating rare, primary hematopoietic cell lineages. Here, we test the feasibility of immunopeptidome profiling from limited numbers of primary purified human regulatory T cells (TReg ), conventional T cells (Tconv ), and activated T cells. The combined T cell immunopeptide dataset reported here contains 13 804 unique HLA ligands derived from 5049 proteins. Of these, more than 700 HLA ligands were derived from 82 proteins that we exclusively identified from TReg -enriched cells. This study 1) demonstrates that primary, lineage-enriched T cell subpopulations recovered from single donors are compatible with immunopeptidome analysis; 2) presents new TReg -biased ligand candidates; and 3) supports immunopeptidome surveys' value for revealing T cell biology that may not be apparent from expression data alone. Taken together, these findings open up new avenues for targeting TReg and abrogating their suppressive functions to treat cancer.


Assuntos
Biomarcadores/análise , Epitopos/metabolismo , Antígenos HLA/metabolismo , Fragmentos de Peptídeos/metabolismo , Linfócitos T/classificação , Linfócitos T/metabolismo , Apresentação do Antígeno/imunologia , Epitopos/imunologia , Antígenos HLA/análise , Antígenos HLA/imunologia , Humanos , Imunoterapia , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Doadores de Tecidos
11.
Proteomics ; 18(12): e1700284, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29505699

RESUMO

Immunotherapy is revolutionizing cancer treatment and has shown success in particular for tumors with a high mutational load. These effects have been linked to neoantigens derived from patient-specific mutations. To expand efficacious immunotherapy approaches to the vast majority of tumor types and patient populations carrying only a few mutations and maybe not a single presented neoepitope, it is necessary to expand the target space to non-mutated cancer-associated antigens. Mass spectrometry enables the direct and unbiased discovery and selection of tumor-specific human leukocyte antigen (HLA) peptides that can be used to define targets for immunotherapy. Combining these targets into a warehouse allows for multi-target therapy and accelerated clinical application. For precise personalization aimed at optimally ensuring treatment efficacy and safety, it is necessary to assess the presence of the target on each individual patient's tumor. Here we show how LC-MS paired with gene expression data was used to define mRNA biomarkers currently being used as diagnostic test IMADETECT™ for patient inclusion and personalized target selection within two clinical trials (NCT02876510, NCT03247309). Thus, we present a way how to translate HLA peptide presentation into gene expression thresholds for companion diagnostics in immunotherapy considering the peptide-specific correlation to its encoding mRNA.


Assuntos
Antígenos de Neoplasias/metabolismo , Antígenos HLA/metabolismo , Imunoterapia , Neoplasias/metabolismo , Fragmentos de Peptídeos/metabolismo , Medicina de Precisão , Proteogenômica/métodos , Apresentação do Antígeno/imunologia , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/imunologia , Tomada de Decisões , Epitopos/imunologia , Epitopos/metabolismo , Antígenos HLA/análise , Antígenos HLA/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Espectrometria de Massas/métodos , Neoplasias/imunologia , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/imunologia , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA Mensageiro/imunologia
12.
Am J Epidemiol ; 187(1): 34-44, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29309515

RESUMO

Breastfeeding, age at introduction of foods, and food diversity in infancy were studied for associations with advanced islet autoimmunity and type 1 diabetes. During 1996--2004, a total of 5,915 newborns with human leukocyte antigen-conferred susceptibility to type 1 diabetes were enrolled in the prospective Finnish Type 1 Diabetes Prediction and Prevention Nutrition Study. Children were assessed at intervals of 3-12 months for the appearance of 4 types of islet autoantibodies and type 1 diabetes up to the age of 15 years. Survival models indicated the 3 variables of interest were not associated with advanced islet autoimmunity or type 1 diabetes in the cohort. Early introduction of solid foods was associated with increased risk of advanced islet autoimmunity in children up to age 3 years (for <3 months vs. >4 months, hazard ratio = 2.33, 95% confidence interval: 1.39, 3.91; for 3-4 months vs. >4 months, hazard ratio = 2.18; 95% confidence interval: 1.38, 3.47) but not in longer follow-up (P for interaction = 0.046). Similar results were observed for age at introduction of roots, cereals, egg, and meat relative to risk of advanced islet autoimmunity. No consistent, long-term associations between infant feeding and advanced islet autoimmunity or type 1 diabetes were observed.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Comportamento Alimentar , Predisposição Genética para Doença , Ilhotas Pancreáticas/imunologia , Adolescente , Fatores Etários , Autoanticorpos/imunologia , Autoimunidade/genética , Aleitamento Materno , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Feminino , Finlândia/epidemiologia , Antígenos HLA/análise , Humanos , Lactente , Alimentos Infantis , Recém-Nascido , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Desmame
13.
Histopathology ; 72(6): 945-954, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29297942

RESUMO

AIMS: Adult T cell leukaemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis. Human leucocyte antigen (HLA) and ß2 microglobulin (ß2M) serve as key molecules in tumour immunity, and their expression is reduced frequently in tumour cells. Programmed cell death (PD)-1/PD-ligand1 (PD-L1) interactions play a role in escape of tumour cells from T cell immunity. Therefore, this study aimed to determine the clinicopathological relevance of HLA and ß2M expressions in ATLL cells and PD-L1 expression in lymphoma or stromal cells and predict the overall survival of patients with ATLL. METHODS AND RESULTS: We analysed a total of 123 biopsy samples from patients newly diagnosed with ATLL by using immunohistochemical analysis. Of the patients enrolled, 91 (74%) were positive for HLA (in cell membrane, 60 patients), 89 (72%) were positive for ß2M (in cell membrane, 54 patients) and 48 (39%) were positive for both HLA and ß2M in the cell membrane (HLAm+ ß2Mm+ ). No significant clinical differences other than prognosis were found between the HLAm+ ß2Mm+ group and the other groups. Immunophenotypical evaluation revealed significantly higher rates of CD30-positive lymphoma cells (P = 0.003) and PD-L1-positive stromal cells in microenvironments (miPD-L1high ) (P = 0.011) of the HLAm+ ß2Mm+ group than in the other groups. The HLAm+ ß2Mm+ group had a significantly better prognosis that the other groups (P = 0.0096), and patients showing HLAm+ ß2Mm+ with miPD-L1high had the most favourable prognosis among all groups. CONCLUSIONS: The membranous expression of HLA and ß2M is likely to reflect the immune response and would be useful to predict prognosis before starting ATLL therapy.


Assuntos
Biomarcadores Tumorais/imunologia , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/análise , Intervalo Livre de Doença , Feminino , Antígenos HLA/análise , Antígenos HLA/biossíntese , Humanos , Estimativa de Kaplan-Meier , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Microglobulina beta-2/análise , Microglobulina beta-2/biossíntese
14.
Transpl Int ; 31(4): 424-435, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29265514

RESUMO

Development of donor-specific antibodies (DSA) after renal transplantation is known to be associated with worse graft survival, yet determining which specificities in which recipients are the most deleterious remains under investigation. This study evaluated the relationship of the complement binding capacity of post-transplant de novo anti-human leukocyte antigen (HLA) antibodies with subsequent clinical outcome. Stored sera from 265 recipients previously identified as having de novo DSA were retested for DSA and their C3d binding capacity using Luminex-based solid-phase assays. Most recipients had anti-HLA class II-reactive DSA (class I = 12.5%, class II = 68.7%, class I and class II = 18.9%). The recipients that had C3d binding DSA (67.5%) had a significantly higher incidence of antibody-mediated rejection and any rejection. They also had significantly lower kidney survival, with the lowest survival in those that had both anti-HLA class I and class II C3d binding DSA. Concurrent biopsy comparison revealed a 96.2% positive predictive value and 47.4% negative predictive value for C4d peritubular capillary (Ptc) deposition. Anti-HLA class I and class II C3d binding DSA carried a twofold and 1.5-fold increased risk of kidney loss, respectively, in multivariate analysis.


Assuntos
Complemento C3d/metabolismo , Antígenos HLA/metabolismo , Transplante de Rim , Imunologia de Transplantes , Adulto , Especificidade de Anticorpos , Complemento C4b/metabolismo , Feminino , Sobrevivência de Enxerto , Antígenos HLA/análise , Humanos , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Nefrite/imunologia , Fragmentos de Peptídeos/metabolismo , Estudos Retrospectivos
15.
Biol Blood Marrow Transplant ; 23(12): 2118-2126, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28807768

RESUMO

The European Group for Blood and Marrow Transplantation (EBMT) risk score has been implemented as an important tool to predict patient outcomes after allogeneic hematopoietic stem cell transplantation. However, to our knowledge, this score has never been applied in cases of single umbilical cord blood transplantation (sUCBT). We retrospectively analyzed 207 consecutive patients with acute leukemia who received sUCBT at our center between February 2011 and December 2015. The probabilities of 3-year overall survival (OS) and leukemia-free survival (LFS) of the entire cohort were 65.0% and 59.8%, respectively, whereas the cumulative incidences of 3-year nonrelapse mortality (NRM) and relapse rate were 19.5% and 20.3%, respectively. In the univariate analysis, a higher EBMT risk score was associated with worse OS and LFS and higher NRM and relapse rate, ranging from 81.7%, 75.9%, 7.3%, and 15.3%, respectively, for patients with a score of 1 to 43.8%, 44.3%, 31.7%, and 23.9%, respectively, for patients with scores of 4 to 6. Hazard ratios of OS, LFS, and NRM all steadily increased for each additional score point. Importantly, the prognostic value of the EBMT risk score on OS, LFS, NRM, and relapse was maintained in the multivariate analysis. Moreover, considering the univariate analysis results of donor-recipient gender and mismatched allele-level HLA-A, -B, -C, and -DRB1 loci on patient outcomes and the fairly strong interaction between time from diagnosis to sUCBT and disease status, we developed a modified sUCBT-EBMT risk score by using degrees of 8-allele HLA match instead of donor type, donor-recipient gender combination, and time from diagnosis to sUCBT, and found that the modified score could also be used as a predictor for patient outcomes after sUCBT. The EBMT risk score is a good predictor of outcomes of patients with leukemia after sUCBT. The modified sUCBT-EBMT risk score can also be used as a pretransplant risk assessment, but this metric still requires further evaluation with a larger cohort.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia/diagnóstico , Medição de Risco/métodos , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Antígenos HLA/análise , Humanos , Lactente , Leucemia/mortalidade , Leucemia/terapia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco/normas , Análise de Sobrevida , Doadores de Tecidos , Adulto Jovem
16.
Med Hypotheses ; 104: 174-177, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28673580

RESUMO

Pro-inflammatory peptides present in wheat and related grains are associated with celiac disease and non-celiac gluten sensitivity. We hypothesize that these peptides induce enteric responses that may exacerbate the gastrointestinal manifestations of graft-versus-host disease after an allogeneic hematopoietic stem cell transplant. Therefore, we propose that a gluten free diet should be tested as a prophylactic and/or therapeutic intervention against gastrointestinal graft-versus-host disease for patients undergoing an allogeneic hematopoietic stem cell transplant.


Assuntos
Mucosa Gástrica/metabolismo , Glutens/toxicidade , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Alelos , Animais , Autoimunidade , Grão Comestível , Gastroenteropatias/etiologia , Gastroenteropatias/imunologia , Antígenos HLA/análise , Humanos , Inflamação , Camundongos , Modelos Teóricos , Transplante Homólogo/efeitos adversos , Triticum
17.
Transfus Med Rev ; 31(3): 183-192, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28385575

RESUMO

The principal theme of the symposium was centered on how the world of regenerative medicine intersects with that of transfusion medicine, with a particular focus on hematopoietic stem cells (HSCs) and stem cell therapies. The symposium highlighted several exciting developments and identified areas where additional research is needed. A revised map of human hematopoietic hierarchy was presented based on the functional and phenotypic analysis of thousands of single stem and progenitor cells from adult bone marrow and fetal liver. These analyses revealed that multipotency is largely restricted to the HSC and multipotent progenitor compartments in adult bone marrow where most progenitors are unipotent, whereas fetal liver contains a large number of distinct oligopotent progenitors. Furthermore, unlike adult bone marrow, multipotency is extended in the downstream progenitors in the hierarchy in the fetal liver stage. Production of platelets ex vivo from HSCs is emerging as a potentially viable option because of advances in culture techniques that combine cytokine mixtures, small molecules, and shear stress. However, limited HSC expansion and low platelet yield from culture-derived megakaryocytes remain problematic. Evidence was presented to support stricter guidelines for transfusion of platelets and red blood cells practices in allogeneic HSC transplant patients, although evidence is often extrapolated from general indications. Basic principles of human leukocyte antigen testing in HSC transplant were described, emphasizing the need for a national (and global) stem cell donor registry. Ongoing research is aimed at improving cellular cryopreservation including the establishment of a new thawing protocol that improves viability of umbilical cord blood CD34+ cells. Umbilical cord blood transplantation practices have also been improved; recent studies suggest noninferior outcomes when patients are transplanted with umbilical cord blood vs a matched adult donor. Finally, mesenchymal stem cell infusion is an example of a cellular therapy useful for immunomodulation. Preclinical trials suggest that mesenchymal stem cells may be effective in managing sepsis. In conclusion, practices and research surrounding HSCs are continuing to evolve rapidly as new information is obtained.


Assuntos
Transfusão de Sangue/métodos , Transplante/métodos , Animais , Antígenos CD34/metabolismo , Bancos de Sangue , Plaquetas/citologia , Canadá , Diferenciação Celular , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Citocinas/metabolismo , Difusão de Inovações , Sangue Fetal/citologia , Antígenos HLA/análise , Antígenos HLA/imunologia , Células-Tronco Hematopoéticas/citologia , Humanos , Megacariócitos/citologia , Células-Tronco Mesenquimais/citologia , Medicina Regenerativa , Sepse/fisiopatologia
18.
Rheumatology (Oxford) ; 56(8): 1282-1292, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28407095

RESUMO

Objectives: To evaluate whether genetic and environmental factors associated with RA in European and Asian ancestry populations are also associated with RA in African ancestry individuals. Methods: A case-control study was undertaken in 197 RA cases and 868 controls of African ancestry (Black African, Black Caribbean or Black British ethnicity) from South London. Smoking and alcohol consumption data at RA diagnosis was captured. Genotyping was undertaken (Multi-Ethnic Genotyping Array) and human leukocyte antigen (HLA) alleles imputed. The following European/Asian RA susceptibility factors were tested: 99 genome-wide loci combined into a genetic risk score; HLA region [20 haplotypes; shared epitope (SE)]; smoking; and alcohol consumption. The SE was tested for its association with radiological erosions. Logistic regression models were used, including ancestry-informative principal components, to control for admixture. Results: European/Asian susceptibility loci were associated with RA in African ancestry individuals. The genetic risk score provided an odds ratio (OR) for RA of 1.53 (95% CI: 1.31, 1.79; P = 1.3 × 10 - 7 ). HLA haplotype ORs in European and African ancestry individuals were highly correlated ( r = 0.83, 95% CI: 0.56, 0.94; P = 1.1 × 10 - 4 ). Ever-smoking increased (OR = 2.36, 95% CI: 1.46, 3.82; P = 4.6 × 10 - 4 ) and drinking alcohol reduced (OR = 0.34, 95% CI: 0.20, 0.56; P = 2.7 × 10 - 5 ) RA risk in African ancestry individuals. The SE was associated with erosions (OR = 2.61, 95% CI: 1.36, 5.01; P = 3.9 × 10 - 3 ). Conclusion: Gene-environment RA risk factors identified in European/Asian ancestry populations are relevant in African ancestry individuals. As modern statistical methods facilitate analysing ancestrally diverse populations, future genetic studies should incorporate African ancestry individuals to ensure their implications for precision medicine are universally applicable.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Artrite Reumatoide/etnologia , Artrite Reumatoide/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/etnologia , Adulto , Grupo com Ancestrais do Continente Africano/etnologia , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Epitopos/análise , Grupo com Ancestrais do Continente Europeu/etnologia , Feminino , Interação Gene-Ambiente , Genótipo , Antígenos HLA/análise , Haplótipos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Fumar/efeitos adversos , Reino Unido
19.
Mycoses ; 60(7): 447-453, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28338245

RESUMO

Pathogenesis of cryptococcosis in the central nervous system (CNS) is a topic of ongoing research, including the mechanisms by which this fungus invades and infects the brain. Astrocytes, the most common CNS cells, play a fundamental role in the local immune response. Astrocytes might participate in cryptococcosis either as a host or by responding to fungal antigens. To determine the infectivity of Cryptococcus neoformans var. grubii and Cryptococcus gattii in a human astrocytoma cell line and the induction of major histocompatibility complex (MHC) molecules. A glioblastoma cell line was infected with C. neoformans var. grubii and C. gattii blastoconidia labelled with FUN-1 fluorescent stain. The percentage of infection and expression of HLA class I and II molecules were determined by flow cytometry. The interactions between the fungi and cells were observed by fluorescence microscopy. There was no difference between C. neoformans var. grubii and C. gattii in the percentage infection, but C. neoformans var. grubii induced higher expression of HLA class II than C. gattii. More blastoconidia were recovered from C. neoformans-infected cells than from C. gattii infected cells. Cryptococcus neoformans var. grubii may have different virulence mechanisms that allow its survival in human glia-derived cells.


Assuntos
Astrócitos/microbiologia , Cryptococcus gattii/crescimento & desenvolvimento , Cryptococcus neoformans/crescimento & desenvolvimento , Linhagem Celular , Citometria de Fluxo , Antígenos HLA/análise , Humanos , Viabilidade Microbiana , Microscopia de Fluorescência
20.
Thromb Res ; 151 Suppl 1: S100-S102, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28262226

RESUMO

In fetal/neonatal alloimmune thrombocytopenia (FNAIT), platelets are destroyed by maternal antibodies directed against fetal/neonate antigens. Thrombocytopenia can be severe and lead to intracranial hemorrhage (ICH) in about 10% of cases. Although three types of antigen groups, presented on platelets [ABO blood group antigens, human leukocyte antigens (HLA) and human platelet antigens (HPA)] are known to be implicated in immune platelet destruction, antibodies against HPA are most commonly involved in FNAIT and hence are the target of extensive research. Awareness of FNAIT by physicians as well as the availability of the most sensitive diagnostic methods capable of detecting a wide range of antibodies are crucial for the diagnosis of FNAIT and the prevention of severe thrombocytopenia and its bleeding risks in subsequent pregnancies.


Assuntos
Antígenos de Plaquetas Humanas/imunologia , Plaquetas/patologia , Trombocitopenia Neonatal Aloimune/diagnóstico , Trombocitopenia Neonatal Aloimune/imunologia , Sistema ABO de Grupos Sanguíneos/análise , Sistema ABO de Grupos Sanguíneos/imunologia , Anticorpos/análise , Anticorpos/imunologia , Antígenos de Plaquetas Humanas/análise , Plaquetas/imunologia , Antígenos HLA/análise , Antígenos HLA/imunologia , Humanos , Recém-Nascido , Trombocitopenia Neonatal Aloimune/patologia
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