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1.
Blood Cancer J ; 11(8): 142, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376633

RESUMO

This study evaluated the safety and immunogenicity of BNT162b2 vaccine in patients with hematological malignancies. Antibodies blocking spike binding to immobilized ACE-2 (NAb) correlated with anti-Spike (S) IgG d42 titers (Spearman r = 0.865, p < 0.0001), and an anti-S IgG d42 level ≥3100 UA/mL was predictive of NAb ≥ 30%, the positivity cutoff for NAb (p < 0.0001). Only 47% of the patients achieved an anti-S IgG d42 level ≥3100 UA/mL after the two BNT162b2 inocula, compared to 87% of healthy controls. In multivariable analysis, male patients, use of B-cell targeting treatment within the last 12 months prior to vaccination, and CD19+ B-cell level <120/uL, were associated with a significantly decreased probability of achieving a protective anti-S IgG level after the second BNT162b2 inoculum. Finally, using the IFN-γ ELISPOT assay, we found a significant increase in T-cell response against the S protein, with 53% of patients having an anti-S IgG-positive ELISPOT after the second BNT162b2 inoculum. There was a correlation between the anti-S ELISPOT response and IgG d42 level (Spearman r = 0.3026, p = 0.012). These findings suggest that vaccination with two BNT162b2 inocula translates into a significant increase in humoral and cellular response in patients with hematological malignancies, but only around half of the patients can likely achieve effective immune protection against COVID-19.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/complicações , COVID-19/imunologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Imunogenicidade da Vacina , SARS-CoV-2/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/administração & dosagem , Comorbidade , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
3.
Clin Transl Immunology ; 9(9): e1171, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005413

RESUMO

Objectives: Haploidentical haematopoietic cell transplantation (Haplo-HCT) using peripheral blood stem cell (PBSC) grafts and post-transplant cyclophosphamide (PTCy) is being increasingly used; however, data on immunological reconstitution (IR) are still scarce. Methods: This retrospective study evaluated T-cell immunological reconstitution in 106 adult patients who underwent allogeneic haematopoietic cell transplantation for haematologic malignancies between 2013 and 2016. Results: At D30, while conventional T cells reached similar median counts in Haplo-HCT recipients (n = 19) and controls (n = 87), γδ and Vδ2+ T-cell median counts were significantly lower in Haplo-HCT recipients and it persists at least until D360 for Vδ2+ T cells. PTCy induces a significant reduction in early γδ and Vδ2+ T-cell proliferation at D  7. At one year, the rate of increase in Epstein-Barr virus (EBV) viral load was significantly higher in Haplo-HCT recipients as compared to controls (61% versus 34%, P = 0.02). In multivariate analysis, a higher γδ T-cell count (> 4.63 µL-1) at D30 was the only independent parameter significantly associated with a reduced risk of increase in EBV viral load (RR 0.34; 95% CI, 0.15-0.76, P = 0.009). Conclusion: Immunological reconstitution of γδ T cells is significantly delayed after Haplo-HCT using PTCy and low-dose ATG and is associated with an increased risk of increase in EBV viral load.

4.
Acta Pharm Sin B ; 10(6): 1061-1072, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32642412

RESUMO

Arsenic trioxide (As2O3) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of As2O3 induced apoptosis of pDCs via mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, As2O3 preferentially inhibited IFN-α secretion as compared to other cytokines such as TNF-α, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, As2O3 induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs' capacity to induce CD4+ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN-α inhibition, and regulatory phenotype induced by As2O3. Collectively, our data suggest that As2O3 could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature.

5.
Cancer Med ; 9(6): 2077-2084, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31991058

RESUMO

BACKGROUND: Daratumumab (Dara), an anti-CD38 monoclonal antibody, has an immunologic mechanism of action through targeting of CD38 expressing immune cells in patients with multiple myeloma (MM). Furthermore, it was recently shown that CD38 upregulation in tumors, is a major mechanism of acquired resistance to antiprogrammed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Therefore, we decided to evaluate the immunomodulatory effects of CD38 blockade by Dara on the PD-L1 expressing immune cells. METHODS: We analyzed CD38 and PD-L1 expression on immune cells at different time points in 18 newly diagnosed MM receiving bortezomib, lenalidomide and dexamethasone, with or without Dara. RESULTS: We first confirmed that CD38 is widely expressed on immune cells, with the strongest expression on plasmacytoid dendritic cells (pDC). Furthermore, Dara induces a strong depletion of pDC in addition to the well-known rapid depletion of natural killer cells. Finally, we found that PD-L1 expression on antigen-presenting cells (APC) increases with MM treatment in patients that did not received Dara, while addition of Dara prevents this increase. CONCLUSION: Overall, our results suggest new mechanisms of action of Dara through depletion of pDC and prevention of PD-L1 upregulation expression on APC. Our finding provides new evidences for development of therapeutic strategies targeting both CD38 and PD-L1/PD-1 pathway in patients with MM.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Células Dendríticas/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , ADP-Ribosil Ciclase 1/antagonistas & inibidores , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/imunologia , Talidomida/farmacologia , Talidomida/uso terapêutico
6.
Bone Marrow Transplant ; 55(3): 570-577, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31558787

RESUMO

Acute graft-versus-host disease (aGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). The majority of aGVHD mouse models are based on radiation conditioning and bone marrow as graft, despite that most allo-HCTs performed now in clinic are based on chemotherapy conditioning and G-CSF mobilized graft. Aiming for a higher translational value, we constructed an MHC major mismatched [C57BL/6 (H-2 Kb) to BALB/c (H-2Kd)] aGVHD mouse model based on busulfan/cyclophosphomide (BU-CY) conditioning and human G-CSF mobilized splenocytes as graft. Allogeneic transplanted mice showed quick and profound donor engraftment. Moreover, there were quick onset (day +7) of typical clinical and histopathological signs of aGVHD, which gradually developed to extensive aGVHD. In addition, CD8+ T cells were the main aGVHD contributing T-cell subtype. No toxicity or GVHD signs were observed in the syngeneic setting. This clinical-relevant model offers a promising platform for future studies on aGVHD.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Fator Estimulador de Colônias de Granulócitos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo
7.
Bone Marrow Transplant ; 55(3): 586-594, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31562397

RESUMO

This retrospective study evaluated the impact of a pre-emptive rituximab (RTX) strategy for Epstein-Barr virus (EBV) reactivation on immune recovery and outcomes of 219 high-risk recipients undergoing allogeneic stem cell transplantation (allo-SCT) for hematological malignancies or bone marrow failure. One-hundred and seven patients received pre-emptive RTX for EBV reactivation (RTX group) and 112 did not (control group). The median onset time of EBV reactivation was 49 days (range, 14-561), including five patients who developed post-transplant lymphoproliferative disorder (EBV-PTLD). RTX and control groups were pair-matched to assess the impact of RTX on all endpoints. In RTX patients, CD19 + B cells were significantly decreased until 1-year post-transplant, so were immunoglobulin levels. Twenty-one patients (17%) developed RTX-related neutropenia. There was, in the RTX group, a trend towards a lower cumulative incidence of chronic GvHD (P = 0.059). Overall survival, progression-free survival, non-relapse mortality, relapse incidence, and incidence of overall infections at 2 years following allo-SCT were comparable in the two groups. We conclude that pre-emptive RTX, despite inducing a delayed B-cell reconstitution and a high risk of RTX-related neutropenia, may be considered as a worthwhile treatment, given the absence of negative impact on post allo-SCT outcomes and a low incidence of EBV-PTLD.


Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Transtornos Linfoproliferativos , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4 , Humanos , Recidiva Local de Neoplasia , Estudos Retrospectivos , Rituximab/uso terapêutico
8.
Eur J Haematol ; 103(1): 10-17, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30958904

RESUMO

OBJECTIVES: This retrospective study analyzed the impact of early cyclosporine A (CsA) initiation (day -3) on the risk of acute graft-vs-host disease (aGvHD) after haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplant cyclophosphamide. METHODS: Sixty-one consecutives patients who underwent Haplo-HCT were analyzed. RESULTS: At day +180, the cumulative incidences of grade II-IV and grade III-IV aGvHD were 39% and 18%, respectively. Patients having a lowest CsA concentration (<301 ng/mL; the cutoff value used to segregate the patients between low and high CsA concentrations) in the first week after Haplo-HCT had a significantly higher risk of grade II-IV aGvHD (P = 0.02), severe grade III-IV aGvHD (P = 0.03), cGvHD (P = 0.02), and extensive cGvHD (P = 0.04). In multivariate analysis, a higher CsA concentration (≥301 ng/mL) during the first week following Haplo-HCT was the only parameter significantly associated with a reduced risk of grade II-IV and grade III-IV aGvHD (RR = 0.21; P = 0.049 and RR < 0.001; P < 0.0001, respectively). We find no correlation between CsA concentration and relapse, non-relapse mortality, progression-free survival, GvHD-free and progression-free survival, or overall survival. CONCLUSIONS: CsA could be initiated early before Haplo-HCT with achievement of high CsA concentration to reduce the risk of aGvHD without any detrimental effect on relapse.


Assuntos
Ciclosporina/administração & dosagem , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/administração & dosagem , Doença Aguda , Adolescente , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Ciclosporina/farmacocinética , Monitoramento de Medicamentos , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/epidemiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Humanos , Imunossupressores/farmacocinética , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Tempo para o Tratamento , Condicionamento Pré-Transplante , Transplante Haploidêntico , Resultado do Tratamento , Adulto Jovem
9.
Ann Rheum Dis ; 78(4): 539-550, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760472

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by widespread fibrosis, microangiopathy and autoantibodies. Follicular helper T (Tfh) cells CD4+CXCR5+PD-1+ cooperate with B lymphocytes to induce the differentiation of plasmocytes secreting immunoglobulins (Ig). Circulating Tfh (cTfh) cells are increased in several autoimmune diseases. However, there are no data about cTfh cells and their interaction with B cells in SSc. The aim of this study was to perform a quantitative and functional analysis of cTfh cells in SSc. METHODS: Using flow cytometry, we analysed cTfh cells from 50 patients with SSc and 32 healthy controls (HC). In vitro coculture experiments of sorted cTfh and B cells were performed for functional analysis. IgG and IgM production were measured by ELISA. RESULTS: We observed that cTfh cell numbers are increased in patients with SSc compared with HC. Furthermore, the increase in cTfh cells was more potent in patients with severe forms of SSc such as diffuse SSc and in the presence of arterial pulmonary hypertension. cTfh cells from patients with SSc present an activated Tfh phenotype, with high expression of BCL-6, increased capacity to produce IL-21 in comparison with healthy controls. In vitro, cTfh cells from patients with SSc had higher capacity to stimulate the differentiation of CD19+CD27+CD38hi B cells and their secretion of IgG and IgM through the IL-21 pathway than Tfh cells from healthy controls. Blocking IL-21R or using the JAK1/2 inhibitor ruxolitinib reduced the Tfh cells' capacity to stimulate the plasmablasts and decreased the Ig production. CONCLUSIONS: Circulating Tfh cells are increased in SSc and correlate with SSc severity. The IL-21 pathway or JAK1/2 blockade by ruxolitinib could be a promising strategy in the treatment of SSc.


Assuntos
Interleucinas/imunologia , Plasmócitos/patologia , Pirazóis/farmacologia , Escleroderma Sistêmico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Feminino , Humanos , Imunofenotipagem , Interleucinas/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/sangue , Estudos Prospectivos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos
10.
Oncoimmunology ; 7(7): e1444411, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900053

RESUMO

Multiple myeloma (MM) results from expansion of abnormal plasma cells in the bone marrow (BM). Previous studies have shown that monocytes play a crucial role in MM pathophysiology. A 6-sulfo LacNAc-expressing population of dendritic cells (Slan-DCs) that overlaps with intermediate and non-classical monocytes in terms of phenotype has been described. Slan-DCs represent a circulating and tissue proinflammatory myeloid population which has been shown to play a role in different cancer contexts, and which exhibits a remarkable plasticity. Herein, we studied Slan-DCs from the BM and blood of MM patients. We performed quantitative and functional analyses of these cells from 54 patients with newly diagnosed, symptomatic MM, 21 patients with MGUS and 24 responding MM patients. We found that circulating Slan-DCs were significantly decreased in MM patients as compared to those of healthy donors or patients with MGUS, while CD14+CD16+ intermediate monocytes accumulate in the BM. Moreover, after activation with TLR7/8 ligand R848, IL-12-producing Slan-DCs from the BM or peripheral blood from MM patients were decreased as compared with healthy donors. We show that MM cell lines or MM cells isolated from patients at diagnosis were able to inhibit the production of IL-12 by Slan-DCs, as well as to shift the phenotype of Slan-DCs towards an intermediate monocyte-like phenotype. Finally, Slan-DCs that have been cultured with MM cells reduced their capacity to induce T cell proliferation and Th1 polarization. We conclude that Slan-DCs represent previously unrecognized players in MM development and may represent a therapeutic target.

11.
PLoS Biol ; 12(8): e1001928, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25136970

RESUMO

Phenotypic heterogeneity can confer clonal groups of organisms with new functionality. A paradigmatic example is the bistable expression of virulence genes in Salmonella typhimurium, which leads to phenotypically virulent and phenotypically avirulent subpopulations. The two subpopulations have been shown to divide labor during S. typhimurium infections. Here, we show that heterogeneous virulence gene expression in this organism also promotes survival against exposure to antibiotics through a bet-hedging mechanism. Using microfluidic devices in combination with fluorescence time-lapse microscopy and quantitative image analysis, we analyzed the expression of virulence genes at the single cell level and related it to survival when exposed to antibiotics. We found that, across different types of antibiotics and under concentrations that are clinically relevant, the subpopulation of bacterial cells that express virulence genes shows increased survival after exposure to antibiotics. Intriguingly, there is an interplay between the two consequences of phenotypic heterogeneity. The bet-hedging effect that arises through heterogeneity in virulence gene expression can protect clonal populations against avirulent mutants that exploit and subvert the division of labor within these populations. We conclude that bet-hedging and the division of labor can arise through variation in a single trait and interact with each other. This reveals a new degree of functional complexity of phenotypic heterogeneity. In addition, our results suggest a general principle of how pathogens can evade antibiotics: Expression of virulence factors often entails metabolic costs and the resulting growth retardation could generally increase tolerance against antibiotics and thus compromise treatment.


Assuntos
Adaptação Fisiológica/genética , Antibacterianos/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Salmonella typhimurium/genética , Salmonella typhimurium/patogenicidade , Adaptação Fisiológica/efeitos dos fármacos , Genes Bacterianos , Mutação/genética , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/fisiologia , Seleção Genética/efeitos dos fármacos , Virulência/efeitos dos fármacos , Virulência/genética
12.
Ann Pathol ; 30(5): 344-9, 2010 Oct.
Artigo em Francês | MEDLINE | ID: mdl-21055521

RESUMO

AIM: To study the composition of foodstuffs (sausage, merguez, chipolata) on microscopic examination. MATERIAL AND METHODS: Six sausages, merguez, and chipolatas, sold in supermarkets were studied. The samples were weighed before and after dehydration to assess the water composition. Foodstuffs specimens were formalin-fixed, paraffin-embedded and analyzed on microscopic examination. Proportions of different tissues were assessed by morphometric analysis. RESULTS: Specimens contained a high proportion of water (40 to 55%). Striated muscular fibers represented from 0.7 to 15.3% for the sausages and the merguez, and from 61 to 76.5% for the chipolatas. Sausages and merguez contained from 43.3 to 49.2% of adipose tissue. All the specimens had fibrous tissue and most of them had small fragments of bone and cartilaginous tissue. Fragments of salivar glands were found in the sausages and fragments of lymphoid tissue were found in merguez. There were neither parasite nor brain tissue. Manufacturer wrote on the label the presence of "meat" with no information about the nature and the proportion of tissues in the foodstuffs specimens. Prices of the foodstuffs were globally correlated to the quantity of muscular fibers in the specimens. CONCLUSION: Pathological studies are not performed in France for the control of foodstuffs. Microscopic analysis could be interesting, as well as biochemical and bacteriological studies, in order to identify the nature and the proportion of tissues involved in the composition of the foodstuffs, to search tissues with potential risk of pathogenic agents transmission, and to search for some parasites.


Assuntos
Análise de Alimentos/métodos , França , Patologia
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