Asunto(s)
Inmunidad Celular/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/inmunología , Purinas/farmacología , Quinazolinonas/farmacología , Linfocitos T/efectos de los fármacos , Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Movimiento Celular/inmunología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/inmunología , Humanos , Inmunidad Celular/genética , Inmunidad Celular/inmunología , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Linfocitos T/inmunología , Linfocitos T/metabolismoAsunto(s)
Biosimilares Farmacéuticos/farmacología , Filgrastim/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Leucemia Mieloide/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Células Madre de Sangre Periférica/efectos de los fármacos , Enfermedad Aguda , Adulto , Femenino , Fármacos Hematológicos/farmacología , Humanos , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Endothelin-1 (ET-1) is a hormone peptide widely expressed and is involved in several biological processes, important not only for normal cell function but also for tumor development, including cell proliferation, invasion, metastasis, angiogenesis and osteogenesis. In accordance, ET-1 was already shown to contribute to the growth and progression of many different solid cancers. We recently demonstrated that ET-1 has a role in the pathogenesis of chronic lymphocytic leukemia (CLL) where it is abnormally expressed. In the context of this malignancy, ET-1 is able to mediate survival, drug-resistance and growth signals in leukemic cells. Previous studies, not conducted in CLL, have shown that ET-1 regulatory mechanisms are numerous and cell specific. Here, we valued the expression of ET-1 in CLL, in relation to DNA methylation but also in response to stimulation of some important pathways for the dialogue between CLL and microenvironment. We found that a high methylation of ET-1 first intron affects the basal expression of ET-1 in CLL. Moreover, we showed that the activation of CD40 or Toll-like receptor (TLR) by extracellular stimuli produces an augment of ET-1 level in CLL cells. Finally, we demonstrated the fundamental role of NF-kB signalling pathway in promoting and maintaining ET-1 expression in CLL cells, both in basal conditions and after CD40 activation.
Asunto(s)
Endotelina-1/genética , Epigénesis Genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD40/metabolismo , Metilación de ADN , Femenino , Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Transducción de Señal , Receptores Toll-Like/metabolismo , Células Tumorales CultivadasRESUMEN
Based upon the clinical behavior of three patients, we suggest that the combination of low-dose Ara-C and all-trans retinoic acid may potentially be effective in some elderly patients, unfit for intensive chemotherapy, affected with NPM1-mutated acute myeloid leukemia without FLT3 mutations, warranting perspective clinical studies in these selected patients.
RESUMEN
BACKGROUND: Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. METHODS AND FINDINGS: By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during high-dose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD): 2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. CONCLUSIONS: Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.
Asunto(s)
Huésped Inmunocomprometido , Leucemia Mieloide Aguda/inmunología , Mucorales/inmunología , Mucormicosis/inmunología , Células Th2/inmunología , Adolescente , Adulto , Anciano , Femenino , Humanos , Leucemia Mieloide Aguda/microbiología , Masculino , Persona de Mediana Edad , Mucormicosis/diagnóstico por imagen , Mucormicosis/microbiología , Radiografía , Células Th2/microbiología , Adulto JovenRESUMEN
Chronic/recurrent behaviour may be encountered in some distinct atypical or malignant lymphoproliferations, while recurrences are not generally observed in reactive/benign lymphadenopathies. We retrospectively analysed a consecutive series of 486 human immunodeficiency virus-negative adults, who underwent lymphadenectomy. Neoplastic and benign/reactive histopathological pictures were documented in 299 (61·5%) and 187 (38·5%) cases, respectively. Of note, seven of the 111 (6·3%) patients with benign lymphadenopathy without well-defined aetiology, showed chronic/recurrent behaviour, without constitutional symptoms. Enlarged lymph nodes were round in shape and hypoechoic, mimicking lymphoma. Reactive follicular hyperplasia and paracortical expansion were observed. Human herpesvirus (HHV)-6B positive staining in follicular dendritic cells (FDCs) was documented in all seven patients. Serological, molecular and immunological examinations suggested HHV-6B reactivation. Among the remaining 104 cases with reactive lymphoid hyperplasia in the absence of well-known aetiology and without recurrences, positivity for HHV-6B on FDCs was found in three cases, whereas in seven further patients, a scanty positivity was documented in rare, scattered cells in inter-follicular regions. Immunohistochemistry for HHV-6A and HHV-6B was invariably negative on 134 lymph nodes, with either benign pictures with known aetiology or malignant lymphoproliferative disorders, tested as further controls. Future studies are warranted to investigate a potential association between HHV-6B reactivation and chronic/recurrent benign lymphadenopathy.
Asunto(s)
Herpesvirus Humano 6/fisiología , Enfermedades Linfáticas/virología , Infecciones por Roseolovirus/complicaciones , Adulto , Anciano , Enfermedad Crónica , Células Dendríticas/patología , Femenino , Humanos , Hiperplasia/virología , Inmunohistoquímica , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Neoplasias/virología , Recurrencia , Estudios Retrospectivos , Activación ViralRESUMEN
Bone marrow has already been described as an enrichment site for several antigen-specific T lymphocytes, but the presence of mould-specific T cells has never been investigated in the bone marrow. We have previously demonstrated that mould-specific T cells emerge in the peripheral blood of patients with invasive fungal infections (IFI) but tend to become undetectable after disease resolution. In seven patients with a history of IFI, we investigated the presence of mould-specific T cells secreting different cytokines in bone marrow and peripheral blood paired samples. The results showed that the frequencies of mould-specific T cells secreting the protective cytokine IFNγ are significantly higher in bone marrow (BM) and are mainly represented by CD8+ T lymphocytes with effector phenotype. A putative disappearance of such protective BM responses after myeloablative therapy could contribute to the increased risk of IFI in hematologic patients.
Asunto(s)
Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Fungemia/inmunología , Hongos/inmunología , Adulto , Anciano , Sangre/inmunología , Estudios de Cohortes , Femenino , Humanos , Interferón gamma/metabolismo , Masculino , Persona de Mediana EdadAsunto(s)
Antineoplásicos/farmacología , Linfoma de Efusión Primaria/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , ARN Interferente Pequeño/farmacología , Proteínas Represoras/antagonistas & inhibidores , Línea Celular Tumoral , Femenino , Humanos , Liposomas , Linfoma de Efusión Primaria/genética , Linfoma de Efusión Primaria/metabolismo , Masculino , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva , ARN Interferente Pequeño/genética , Proteínas Represoras/biosíntesisAsunto(s)
Anemia Aplásica/diagnóstico , Anemia Aplásica/epidemiología , Leucemia/diagnóstico , Leucemia/epidemiología , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Respirovirus/epidemiología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Aplásica/complicaciones , Anemia Aplásica/terapia , Femenino , Humanos , Leucemia/complicaciones , Leucemia/terapia , Masculino , Persona de Mediana Edad , Virus de la Parainfluenza 3 Humana/fisiología , Pronóstico , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Virus Sincitiales Respiratorios/fisiología , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/epidemiología , Infecciones por Respirovirus/complicaciones , Infecciones por Respirovirus/diagnóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenAsunto(s)
Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Proteínas Nucleares/genética , Anciano , Biopsia , Médula Ósea/patología , Transformación Celular Neoplásica/genética , Análisis Mutacional de ADN , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Trastornos Mieloproliferativos/diagnóstico , NucleofosminaAsunto(s)
Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Linfocitos T Citotóxicos/inmunología , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Femenino , Humanos , Mesilato de Imatinib , Memoria Inmunológica , Inmunofenotipificación , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Inducción de Remisión , Linfocitos T Citotóxicos/metabolismoRESUMEN
Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1-3glucan, ß1-3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA.
Asunto(s)
Antígenos Fúngicos/inmunología , Aspergilosis/sangre , Aspergillus/inmunología , Hematología , Adolescente , Adulto , Anciano , Aspergillus/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Especificidad de la Especie , Linfocitos T/inmunología , Adulto JovenRESUMEN
Mucorales-specific T cells were investigated in 28 hematologic patients during the course of their treatment. Three developed proven invasive mucormycosis (IM), 17 had infections of known origin but other than IM, and 8 never had fever during the period of observation. Mucorales-specific T cells could be detected only in patients with IM, both at diagnosis and throughout the entire course of the IM, but neither before nor for long after resolution of the infection. Such T cells predominantly produced IL-4, IFN-γ, IL-10, and to a lesser extent IL-17 and belonged to either CD4(+) or CD8(+) subsets. The specific T cells that produced IFN-γ were able to directly induce damage to Mucorales hyphae. None of the 25 patients without IM had Mucorales-specific T cells. Specific T cells contribute to human immune responses against fungi of the order Mucorales and could be evaluated as a surrogate diagnostic marker of IM.
Asunto(s)
Biomarcadores , Mucorales/inmunología , Mucormicosis , Linfocitos T/inmunología , Linfocitos T/microbiología , Humanos , Inmunofenotipificación , Mucormicosis/diagnóstico , Mucormicosis/epidemiología , Mucormicosis/inmunología , Factores de RiesgoAsunto(s)
Trasplante de Órganos/efectos adversos , Polimorfismo de Nucleótido Simple , Sarcoma de Kaposi/genética , Factor A de Crecimiento Endotelial Vascular/genética , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Herpesvirus Humano 8/patogenicidad , Humanos , Italia , Desequilibrio de Ligamiento , Modelos Logísticos , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Regiones Promotoras Genéticas , Medición de Riesgo , Factores de Riesgo , Sarcoma de Kaposi/virología , Resultado del Tratamiento , Adulto JovenRESUMEN
Clinical charts from 63 consecutive highly immunocompromised haematologic patients presenting with pulmonary nodular lesions on CT scan, classified as either probable or possible invasive fungal disease (IFD) according to the revised EORTC/MSG classification, were retrospectively studied. Histopathological analysis of lung tissues, available for 23 patients, demonstrated proven IFD in 17 cases (14 invasive aspergillosis and 3 invasive zygomycosis), diffuse alveolar damage in one and organising pneumonia (OP) in five cases. In the OP cases, three of which have been defined as probable IFD according to EORTC/MSG classification, extensive immunohistochemical, molecular and immunological analyses for fungi were negative. Our case descriptions extend the notion that OP may be encountered as a distinct histopathological entity in pulmonary nodular lesions in patients with leukaemia with probable/possible IFD.
Asunto(s)
Neumonía en Organización Criptogénica/diagnóstico , Neumonía en Organización Criptogénica/etiología , Leucemia Mieloide Aguda/complicaciones , Enfermedades Pulmonares Fúngicas/diagnóstico , Enfermedades Pulmonares Fúngicas/etiología , Anciano , Líquido del Lavado Bronquioalveolar/microbiología , Diagnóstico Diferencial , Femenino , Humanos , Huésped Inmunocomprometido , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/etiología , Leucemia Mieloide Aguda/inmunología , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/etiología , Estudios Retrospectivos , Cigomicosis/diagnóstico , Cigomicosis/etiologíaAsunto(s)
Enfermedad de Castleman/complicaciones , Herpesvirus Humano 6/genética , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/virología , Síndrome POEMS/complicaciones , Anciano , Enfermedad de Castleman/virología , ADN Viral/metabolismo , Femenino , Herpesvirus Humano 8/metabolismo , Humanos , Sistema Inmunológico , Síndrome POEMS/virología , Patología Molecular , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADNRESUMEN
Imatinib mesylate has been demonstrated to allow the emergence of T cells directed against chronic myeloid leukemia cells. A total of 10 Philadelphia chromosome-positive acute lymphoblastic leukemia patients receiving high-dose imatinib mesylate maintenance underwent long-term immunological monitoring (range, 2-65 months) of (p190)BCR-ABL-specific T cells in the bone marrow and peripheral blood. (p190)BCR-ABL-specific T lymphocytes were detected in all patients, more frequently in bone marrow than in peripheral blood samples (67% vs 25%, P < .01) and resulted significantly associated with lower minimal residual disease values (P < .001), whereas absent at leukemia relapse. Specific T cells were mainly effector memory CD8(+) and CD4(+) T cells, producing interferon-gamma, tumor necrosis factor-alpha, and interleukin-2 (median percentage of positive cells: 3.34, 3.04, and 3.58, respectively). Cytotoxic subsets able to lyse BCR-ABL-positive leukemia blasts also were detectable. Whether these autologous (p190)BCR-ABL-specific T cells may be detectable under other tyrosine-kinase inhibitors, expanded ex vivo, and exploited for immunotherapy remains to be addressed.