RESUMO
Matching for HLA-A, -B, -C, and -DRB1 loci (8/8 match) is currently the gold standard for unrelated donor hematopoietic cell transplantation (HCT). In Europe, patients are also matched at the HLA-DQB1 loci (10/10 match). However, there is increasing evidence that matching at HLA-DRB3/4/5 loci may help to lower transplant-related morbidity and mortality. We therefore investigated the impact of HLA-DRB3/4/5 mismatches on outcomes in 1975 patients who received a first 10/10 matched unrelated donor (MUD) HCT in France from 2000 to 2012 for a hematological malignancy. High-resolution typing was performed at HLA-A, -B, -C, -DRB1, -DQB1, -DPB1, and -DRB3/4/5 loci for all donor/recipient pairs. Compared with DRB3/4/5-matched pairs, patients who received a MUD HCT from a DRB3/4/5 mismatched donor had a significantly increased risk of grade II-IV acute graft-versus-host disease (aGVHD) (Adjusted Hazard Ratio (HR) 1.43 (1.07 to 1.90)) associated with lower graft-versus-host disease-free and relapse-free survival (GRFS) (Adjusted HR 1.20 (1.02 to 1.42)). Conversely, we observed no differences in terms of chronic GVHD, nonrelapse mortality, relapse and overall survival. However, we believe that patients stand to benefit from DRB3/4/5 loci being considered for unrelated donor selection to improve GRFS and then quality of life after unrelated HCT.
RESUMO
In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country with the purpose of offering careful analysis of published studies on clinical practice issues that remain to be disputed. This article addresses the impact of HLA and KIR gene polymorphism on the outcome of the transplantation in order to optimize unrelated donor selection.
Assuntos
Seleção do Doador/normas , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade/genética , Histocompatibilidade/genética , Polimorfismo Genético , Receptores KIR/genética , Alelos , França , Genótipo , Histocompatibilidade/imunologia , Antígenos de Histocompatibilidade/imunologia , Humanos , Receptores KIR/imunologia , Sociedades Médicas , Resultado do TratamentoRESUMO
The interplay between immune recovery, cytomegalovirus (CMV)-reactivation, CMV-driven immunity and graft-versus-leukaemia effect (GVL) was analysed in 108 children (median age: 8 years) who underwent haematopoietic-stem cell transplantation (HSCT) for acute leukaemia. Follow-up was 2 years unless death or relapse occurred. CMV-polymerase chain reaction (PCR) was programmed weekly until month +3 post-HSCT. Immunomonitoring consisted of sequential lymphocyte subset enumerations and analyses of T-cell proliferative and γ-interferon responses to CMV and to adenovirus. In the 108 recipients, the 2-year relapse rate (RR) was 25% (median time to onset 4·5 months; range: 24 d-17 months). CMV reactivation occurrence was 31% (median time to onset 26 d). Donor/recipient CMV serostatus did not influence RR. Among the 89 recipients disease-free after day +120, i) early CMV-reactivation before day +30 was more frequent (P = 0·01) in the relapse recipient group opposed to the non-relapse group. ii) CD8(+) /CD28(-) and CD4(+) CD45RA(-) T-cell expansions induced by CMV did not influence RR, iii) Recovery of anti-CMV and also anti-adenovirus immunity and of naïve CD4(+) T-cells was faster in the non-relapse group (P = 0·008; 0·009 and 0·002 respectively). In contrast to adult acute myeloid leukaemia, CMV reactivation was associated with increased RR in this paediatric series. Accelerated overall immune recovery rather than CMV-driven immunity had a favourable impact on RR.
Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Efeito Enxerto vs Leucemia/imunologia , Leucemia/imunologia , Adolescente , Criança , Pré-Escolar , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/complicações , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunidade Celular , Lactente , Recém-Nascido , Leucemia/complicações , Leucemia/terapia , Masculino , Recidiva , Estudos Retrospectivos , Fatores de Risco , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Viremia/complicações , Viremia/imunologia , Ativação ViralRESUMO
Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. To analyze the effect of anti-HLA antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using Luminex™ platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Among 62 recipients (23%) who had anti-HLA antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA antibodies (DSA) (7 were donor-specific anti-HLA antibodies for single unrelated cord blood transplant and 7 for double unrelated cord blood transplant). Donor specific anti-HLA antibodies threshold ranged from 1620-17629 of mean fluorescence intensity (MFI). Cumulative incidence of Day-60 neutrophil engraftment was 76%: 44% for recipients with donor specific anti-HLA antibodies and 81% in those without donor specific anti-HLA antibodies (P=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor specific anti-HLA antibodies and 32% in those without antibodies (P=0.06). The presence of donor specific anti-HLA antibodies was associated with a trend for decreased survival rate (42% vs. 29%; P=0.07). Donor specific anti-HLA antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient's screening for donor specific anti-HLA antibodies before unrelated cord blood transplantation is recommended before choosing an HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit for which the patient has donor specific anti-HLA antibodies.
Assuntos
Autoanticorpos/sangue , Sobrevivência de Enxerto/imunologia , Antígenos HLA/sangue , Transplante de Células-Tronco Hematopoéticas/tendências , Doadores de Tecidos , Condicionamento Pré-Transplante/tendências , Adolescente , Adulto , Idoso , Autoanticorpos/biossíntese , Criança , Pré-Escolar , Feminino , Sangue Fetal/citologia , Sangue Fetal/imunologia , Seguimentos , França , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Histocompatibilidade/genética , Histocompatibilidade/imunologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sociedades Médicas/tendências , Taxa de Sobrevida/tendências , Condicionamento Pré-Transplante/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
Immunity induced by influenza vaccines following hematopoietic stem-cell transplantation (HSCT) is poorly understood. Here, 14 pediatric recipients (mean age: 6 years) received H1N1 (n=9) or H1N1/H3N2 (n=5) vaccines at a median of 5.7 months post-HSCT (HLA-identical related bone-marrow graft: 10/14). Fourteen clinically-matched non-vaccinated recipients were included as controls. Cellular response to vaccination was assessed by a T-cell proliferation assay. Humoral response was assessed by H1N1-specific antibody titration. IL2 and IFNγ responses to influenza were also evaluated by an intracellular cytokine accumulation method for some of the recipients. Higher proliferative responses to H1N1 (p=0.0001) and higher H1N1-specific antibody titers (p<0.02) were observed in vaccines opposed to non-vaccinated recipients. In some cases, proliferative responses to H1N1 developed while at the same time antibody titers did not reach protective (≥1:40) levels. Most recipients vaccinated with only the H1N1 strain had proliferative responses to both H1N1 and H3N2 (median stimulation index H1N1: 96, H3N2: 126 in responders). Finally, IL2 responses predominated over IFNγ responses (p<0.02) to influenza viruses in responders. In conclusion, H1N1 vaccination induced substantial cell-mediated immunity, and to a lesser extent, humoral immunity at early times post-HSCT. H1N1/H3N2 T-cell cross-reactivity and protective (IL2) rather than effector (IFNγ) cytokinic profiles were elicited.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunidade Celular , Imunidade Humoral , Vacinas contra Influenza/imunologia , Adolescente , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Humanos , Lactente , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/administração & dosagem , MasculinoRESUMO
BACKGROUND: Distinguishing latent tuberculosis (LTB) from tuberculosis (TB) disease may be challenging in children. Here, we analyzed cytokine profiles that can distinguish the two infection stages in a nonendemic country (France). METHODS: Immunocompetent children with LTB (n = 6) or TB disease (n = 8) (median age: 6.2 and 5.7 years, respectively) were analyzed. Four young uninfected children were included as controls. A Luminex assay evaluated cytokine responses to Mycobacterium tuberculosis antigens. RESULTS: Poor interleukin-4 (IL-4) and IL-10 responses precluded analysis of these cytokines. Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-2, and T-helper type 1 (Th1) cytokines and IL-5, IL-13, T-helper type 2 (Th2) cytokines were simultaneously induced by antigens in 14/14 infected but 0/4 uninfected children. Th1 cytokine levels were similar in LTB and TB disease: IFN-γ: 12,254 and 10,495 pg/ml; IL-2: 2,097 and 1,869 pg/ml; and TNF-α: 1,020 and 2,875 pg/ml, respectively. Th2 cytokine levels were similar and even higher in LTB than in TB disease: IL-5: 23 and 10 pg/ml; IL-13: 284 and 109 pg/ml, respectively. Positive correlation of cytokine levels, whether Th1 or Th2, was observed. Higher (P = 0.008) TNF-α/IL-2 ratios distinguished 6/8 active TB disease cases from 6/6 LTB cases. CONCLUSION: TNF-α/IL-2 ratio may discriminate TB disease from LTB in immunocompetent children. Larger studies in TB endemic settings must verify these results.
Assuntos
Imunocompetência , Testes Imunológicos , Interleucina-2/sangue , Tuberculose Latente/diagnóstico , Mycobacterium tuberculosis/imunologia , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Testes de Liberação de Interferon-gama , Tuberculose Latente/sangue , Tuberculose Latente/imunologia , Masculino , Mycobacterium tuberculosis/isolamento & purificação , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Escarro/microbiologia , Teste Tuberculínico , Tuberculose/sangue , Tuberculose/imunologiaRESUMO
In unrelated hematopoietic stem cell transplantation (HSCT), the prediction of donor search outcome at the time of search initiation is of great value for the physicians to delineate the strategy of patient care. The probability of finding an unrelated donor is high for patients who carry at least 1 of the 10 most common HLA haplotypes in Caucasians. As only 10% to 20% patients respond to this criterion, here we aimed at finding additional common haplotypes to improve the prediction of a successful search. HLA broad HLA-A/B/DRB1 haplotypes that were observed with frequencies ≥0.19% in patient families of European origin and that split into ≤2 predominant 4-digit HLA-A/B/C/DRB1/DQB1 haplotypes were considered as common. Carriage of at least 1 of those in 168 patients of various geographic areas with no family donor was confronted to the chance of finding ≥9/10 HLA-matched unrelated donors. Fifty common 4-digit haplotypes were identified. A higher (P < 5 × 10(-6)) chance of finding a suitable donor was found for 55 of 170 (32%) recipients that carried at least 1 of these common haplotypes. Up to now, estimates classified patients into ≥3 groups of probability with ≥1 intermediate group of poor utility for the clinicians. Considering carriage of these common haplotypes together with the frequencies of alleles and of B/C and DRB1/DQB1 associations, which are carried by patient HLA haplotypes, we could classify the patients into 2 groups of probability with a 98% and 26% chance of finding a donor, respectively. Prediction of search outcome could be improved by including the 50 most common HLA haplotypes in the current approaches.
Assuntos
Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Doadores de Tecidos , Alelos , Criança , Família , Antígenos HLA/imunologia , Haplótipos , Humanos , Resultado do TratamentoRESUMO
The uncommon C77G polymorphism of the Protein-Tyrosine Phosphatase (PTPRC) gene (PTPRC; previously termed CD45) could confer an increased risk of immunopathology. This study compared the outcome of children following human leucocyte antigen-matched unrelated haematopoïetic-stem cell transplantations (HSCT) from donors carrying (C77G cases: n = 8) or not (controls: n = 36) the PTPRC C77G polymorphism. Transmission of the PTPRC C77G polymorphism through the graft was suggested by unusual CD45RA phenotype in the donors and/or in the recipients after, but not before HSCT. Restriction-Fragment Length Polymorphism and sequencing confirmed the polymorphism. Overall survival rates were similar in C77G cases and controls (63% vs. 61%). Acute leukaemia relapse tended to be less frequent in C77G cases (0% vs. 32%; P = 0·09). Among recipients surviving ≥ 30 d, acute GVHD (aGVHD) ≥ grade 2 tended to be more frequent (100% vs. 58%; P = 0·07) and the rate of steroid-refractory or -dependant aGVHD higher (67% vs. 28%) in C77G cases. Finally, extensive chronic GVHD tended to occur more frequently (40% vs. 9%) in C77G cases. Recovery of lymphocyte subsets and virus-specific CD4 was similar in C77G cases and controls while interleukin 2 (IL2)-responses through CD3 stimulation were higher in C77G cases (P = 0·004). In conclusion, HSCT from PTPRC C77G donors could increase GVHD risk without compromising overall survival. Altered IL2-responses could be involved in this process.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia/terapia , Antígenos Comuns de Leucócito/genética , Doadores de Tecidos , Adolescente , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Feminino , Genótipo , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Humanos , Imunofenotipagem , Lactente , Antígenos Comuns de Leucócito/metabolismo , Masculino , Fito-Hemaglutininas/imunologia , Polimorfismo de Fragmento de Restrição , Resultado do TratamentoRESUMO
Age-related changes in memory CD4 T cells (CD4) are poorly known. To address this issue, CD4 proliferative and cytokine responses to an anti-CD3 monoclonal (CD3), to cytomegalovirus (CMV), and to adenovirus (AdV) were assessed in 57 children (age, 0.07-17.16 y) and 17 adults. Results showed i) accumulation of memory CD4 with aging, with 2-3 times more central-memory T cell (TCM; CD45RA/CD62L) than effector-memory T cell (TEM; CD45RA/62L) CD4 at any age. ii) In children older than 2 y, CMV-specific CD4-secreting IFNγ alone predominated over CD4-secreting IL2 + IFNγ and a continuous increase, with aging, in IFNγ responses to the virus was observed. In contrast, in AdV infection, CD4-secreting IL2 + IFNγ predominated and IFNγ responses to the virus reached adult levels from 3 y of age. iii) In children aged 0-2 y, lower total IFNγ responses to CMV (p < 0.02), AdV (p = 0.05), and CD3 (p < 0.01) and lower IFNγ + IL2-responses (p = 0.1, p < 0.02, p < 0.05, respectively) contrasted with no decrease in CD4-secreting IFNγ alone. Defective proliferative responses to AdV (p = 0.03) were also observed. In conclusion, the development of memory CD4 differed in acute AdV and persistent CMV infections. Young age seemed to depress mostly polyfunctional (IL2 + IFNγ secreting) CD4 in both infections.
Assuntos
Adenoviridae/imunologia , Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Citomegalovirus/imunologia , Memória Imunológica , Adolescente , Adulto , Fatores Etários , Anticorpos Monoclonais , Complexo CD3/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/virologia , Proliferação de Células , Criança , Pré-Escolar , França , Humanos , Lactente , Recém-Nascido , Interferon gama/metabolismo , Interleucina-2/metabolismo , Selectina L/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Ativação LinfocitáriaRESUMO
The nature of adenovirus (AdV)-specific T cells that could best predict the capacity of immunocompromised host to fight AdV is unclear. To this aim, 47 pediatric patients were enrolled for at least 3 months either at allogeneic bone marrow transplantation (BMT) (23 genoidentical, 18 unrelated of which 9 were 10/10 and 9 were 9/10 HLA-matched) or at unrelated cord blood transplantation (n = 6). Enumeration of AdV-specific CD4 T cells secreting cytokines (flow cytometry) and proliferative responses to AdV ((3)HT-incorporation) were compared to AdV-DNAemia. A total of 44/47 patients did not evidence AdV-DNAemia. Thirty-two of 44 (73%) developed CD4-mediated interferon-gamma (IFN-γ) responses to AdV (median 0.36 CD4/µL of blood) since the first month post-HSCT (n = 11: 8 genoidentical and 3 unrelated) or the third month (n = 21 additional patients). At 3 months, both incidence and level intensities of AdV-specific CD4 appeared similar in genoidentical and unrelated BMT (70% and 80%; 0.36 and 0.21 CD4/µL, respectively) and not statistically different from age-matched controls (76%; 1.35 CD4/µL), whereas cord blood transplanted patients exhibited similar incidence but higher level intensities (67%; 1.49 CD4/µL). Polyfunctional (IL2 + IFN-γ) and proliferative responses appeared later, after the third month. Three of 4 9/10 HLA-matched unrelated HSCT that did not develop immunity to AdV presented chemotherapy-resistant AdV-DNAemia at 3 to 5 months post-hematopoietic stem cell transplantation (HSCT). Two were successfully treated with AdV-specific CTL infusion. Monitoring, since month 1 post-HSCT, of IFN-γ-secreting AdV-specific CD4 appears suitable for early detection of at-risk patients especially in 9/10 HLA-matched unrelated HSCT and preferable to monitoring of more delayed IL2- and proliferative responses.
Assuntos
Infecções por Adenoviridae , Adenoviridae/imunologia , Linfócitos T CD4-Positivos/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , DNA Viral/sangue , Doenças Hematológicas , Transplante de Células-Tronco Hematopoéticas , Imunidade Celular , Infecções por Adenoviridae/sangue , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/terapia , Adolescente , Linfócitos T CD4-Positivos/metabolismo , Criança , Pré-Escolar , DNA Viral/imunologia , Feminino , Doenças Hematológicas/sangue , Doenças Hematológicas/imunologia , Doenças Hematológicas/terapia , Humanos , Lactente , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-2/sangue , Interleucina-2/imunologia , Masculino , Estudos Retrospectivos , Transplante HomólogoAssuntos
Agamaglobulinemia/diagnóstico , Anticorpos Monoclonais/farmacologia , Linfócitos B/imunologia , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos/farmacologia , Linfopoese/imunologia , Agamaglobulinemia/imunologia , Agamaglobulinemia/metabolismo , Anticorpos Monoclonais Murinos , Linfócitos B/efeitos dos fármacos , Humanos , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Lactente , Leucemia Mielomonocítica Juvenil/cirurgia , Linfopoese/efeitos dos fármacos , Masculino , Rituximab , Condicionamento Pré-TransplanteRESUMO
BACKGROUND: Persistent low CD4(+) cell counts are observed in 5%-27% of patients treated for human immunodeficiency virus (HIV)-1 infection despite their having prolonged undetectable plasma viral loads. METHODS: To understand the possible mechanisms of this discordant immunological situation, a prospective transsectional case-control study was designed. HIV-1-infected subjects who had a plasma viral load <200 copies/mL for >1 year were considered to be case patients if their CD4(+) cell count was <250/mm(3); control patients had CD4(+) cell counts >500/mm(3) and were matched by sex, age, and nadir CD4(+) cell count to case patients. T cell proliferation after stimulation with various antigens, T cell subset counts, T cell rearrangement excision circles (TRECs), T cells undergoing apoptosis, cytokines influencing apoptosis, and cellular proviral DNA and plasma viral RNA persistence were assessed. RESULTS: Compared with the 19 control patients, the 19 case patients had undistinguishable lymphoproliferative responses to candidin and cytomegalovirus, fewer naive CD4(+) cells (CD45RA(+)62L(+), 23%+/-13% vs. 47%+/-14%; P<.0001), lower thymic output (1.28 vs. 3.95 TRECs/microL of blood; P=.0015), increased cell death by apoptosis (spontaneous, 23.2%+/-8.3% vs. 11.9%+/-8.4% [P=.02]; Fas induced, 38.6%+/-13.7% vs. 16.4%+/-8.0% [P=.004]), higher levels of plasma soluble tumor necrosis factor receptor II (9.6 vs. 5.3 ng/mL; P=.0058), and undistinguishable plasma HIV-1 and cellular proviral DNA loads. CONCLUSIONS: The mechanisms responsible for the low-level regeneration of CD4(+) cells involve, at least, deficiency in the regeneration of central CD4(+) cells and excessive apoptosis.
Assuntos
Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/fisiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Adulto , Antígenos Virais , Apoptose , Linfócitos T CD8-Positivos/fisiologia , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Infecções por HIV/virologia , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/sangue , Timo/citologia , Fatores de Tempo , Carga ViralRESUMO
Primary infection with cytomegalovirus (CMV) in immunocompetent hosts is accompanied with activation and differentiation of naive CD8(+) T cells to effector/memory cells secreting interferon-gamma (IFN-gamma). Alteration of these responses during the perinatal period is suggested by a higher rate of CMV diseases in congenital infection. For addressing this issue, immunologic investigations were performed in 15 fetuses (22-36 wk of gestation) with documented congenital CMV infection. Results show that cellular immune responses can be detected as soon as the 22nd week of gestation (the youngest fetus analyzed). Compared with age-matched control subjects, infected fetuses evidence a dramatic increase in the percentages of activated and terminally differentiated CD8 T cells. Indeed, median percentages (interquartile range) of HLA-DR(+) and of CD28(-)CD8(+) T cells were 24% (19-34) and 38% (24-52), respectively in infected fetuses versus 3% (0-4) for each subset in control subjects. In addition, the percentages of T cells secreting IFN-gamma after in vitro stimulation with phorbol myristate acetate and ionomycin was significantly higher in infected fetuses [10% (5-25)] than in healthy fetuses [0.8% (0.6-1.2)] with IFN-gamma being mostly secreted by CD8(+) T cells and to a lesser extend by CD4(+) T cells. These cellular immune responses have clear similarities with responses previously reported in adults. Cellular immunity to CMV, however, might not be fully functional in fetuses. Indeed, the number of T cells capable of secreting IFN-gamma is strikingly lower after in vitro stimulation with the CMV-specific antigen than after in vitro stimulation with phorbol myristate acetate/ionomycin that bypasses signaling through the T-cell receptor.
Assuntos
Linfócitos T CD8-Positivos/virologia , Infecções por Citomegalovirus/imunologia , Feto/imunologia , Feto/virologia , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinógenos/farmacologia , Diferenciação Celular/imunologia , Feminino , Sangue Fetal/citologia , Sangue Fetal/imunologia , Humanos , Memória Imunológica/imunologia , Interferon gama/metabolismo , Ionomicina/farmacologia , Ionóforos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos , Gravidez , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Mutations of the AML1 gene are frequent molecular abnormalities in minimally differentiated acute myeloblastic leukemia (M0 AML), a rare type of AML. In this retrospective multicenter study, morphologic, immunophenotypical, cytogenetic, and molecular features of 59 de novo M0 AML cases were analyzed and correlated to AML1 mutations. Point mutations of AML1 gene were observed in 16 cases (27%). They were correlated with higher white blood cell (WBC) count (P =.001), greater marrow blast involvement (P =.03), higher incidence of immunoglobulin H/T-cell receptor (IgH/TCR) gene rearrangement (P <.0001), and with a borderline significant lower incidence of complex karyotypes. In the 59 patients, FLT3 mutations were the only significant prognostic factors associated with short survival.