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1.
Yonsei Med J ; 61(9): 774-779, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882761

RESUMO

PURPOSE: Histiocytic and dendritic cell neoplasms are rare hematologic tumors. This study aimed to describe the epidemiologic features of the entire spectrum of histiocytic and dendritic cell neoplasms, including clinicopathological variables and patient outcomes. MATERIALS AND METHODS: We comprehensively reviewed 274 patients who were diagnosed with histiocytic and dendritic neoplasms at Severance Hospital, Seoul, South Korea between 1995 and 2018. RESULTS: The most common neoplasm was Langerhans cell histiocytosis (LCH), followed by dermal xanthogranuloma. Among non-LCH sarcomas, histiocytic sarcoma (HS) showed a relatively high prevalence, followed by follicular dendritic cell sarcoma (FDCS). Disseminated juvenile xanthogranuloma (DJG), Erdheim-Chester disease (ECD), indeterminate dendritic cell tumor (IDCT), and interdigitating dendritic cell sarcoma (IDCS) rarely occurred. Generally, these tumors presented in childhood, although the non-LCH sarcoma (HS/FDCS/IDCS/IDCT) group of tumors and ECD occurred in late adulthood. Multiorgan involvement and advanced Ann-Arbor stage, as well as recurrence and death of disease, were not uncommon. The non-LCH sarcoma group had the worst overall survival, compared to the DJG, ECD, and LCH groups. CONCLUSION: Our findings indicate that histiocytic and dendritic cell neoplasms exhibit heterogeneous epidemiologic characteristics and that some patients may have unfavorable outcomes, especially those with non-LCH sarcoma.


Assuntos
Células Dendríticas/patologia , Histiócitos/patologia , Transtornos Histiocíticos Malignos/patologia , Sarcoma Histiocítico/patologia , Adulto , Criança , Sarcoma de Células Dendríticas Foliculares/epidemiologia , Sarcoma de Células Dendríticas Foliculares/patologia , Feminino , Transtornos Histiocíticos Malignos/epidemiologia , Sarcoma Histiocítico/epidemiologia , Histiocitose de Células de Langerhans/epidemiologia , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Prevalência , República da Coreia/epidemiologia , Seul , Xantogranuloma Juvenil/epidemiologia , Xantogranuloma Juvenil/patologia
2.
Immunity ; 53(4): 864-877.e5, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32791036

RESUMO

The SARS-CoV-2 pandemic has resulted in millions of infections, yet the role of host immune responses in early COVID-19 pathogenesis remains unclear. By investigating 17 acute and 24 convalescent patients, we found that acute SARS-CoV-2 infection resulted in broad immune cell reduction including T, natural killer, monocyte, and dendritic cells (DCs). DCs were significantly reduced with functional impairment, and ratios of conventional DCs to plasmacytoid DCs were increased among acute severe patients. Besides lymphocytopenia, although neutralizing antibodies were rapidly and abundantly generated in patients, there were delayed receptor binding domain (RBD)- and nucleocapsid protein (NP)-specific T cell responses during the first 3 weeks after symptoms onset. Moreover, acute RBD- and NP-specific T cell responses included relatively more CD4 T cells than CD8 T cells. Our findings provided evidence that impaired DCs, together with timely inverted strong antibody but weak CD8 T cell responses, could contribute to acute COVID-19 pathogenesis and have implications for vaccine development.


Assuntos
Betacoronavirus/patogenicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus/imunologia , Hipertensão/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Convalescença , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Complicações do Diabetes , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/virologia , Progressão da Doença , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/virologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Monócitos/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Índice de Gravidade de Doença
4.
PLoS One ; 15(5): e0232432, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365067

RESUMO

CR3 and CR4, the leukocyte specific ß2-integrins, involved in cellular adherence, migration and phagocytosis, are often assumed to have similar functions. Previously however, we proved that under physiological conditions CR4 is dominant in the adhesion to fibrinogen of human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs). Here, using inflammatory conditions, we provide further evidence that the expression and function of CR3 and CR4 are not identical in these cell types. We found that LPS treatment changes their expression differently on MDMs and MDDCs, suggesting a cell type specific regulation. Using mAb24, specific for the high affinity conformation of CD18, we proved that the activation and recycling of ß2-integrins is significantly enhanced upon LPS treatment. Adherence to fibrinogen was assessed by two fundamentally different approaches: a classical adhesion assay and a computer-controlled micropipette, capable of measuring adhesion strength. While both receptors participated in adhesion, we demonstrated that CR4 exerts a dominant role in the strong attachment of MDDCs. Studying the formation of podosomes we found that MDMs retain podosome formation after LPS activation, whereas MDDCs lose this ability, resulting in a significantly reduced adhesion force and an altered cellular distribution of CR3 and CR4. Our results suggest that inflammatory conditions reshape differentially the expression and role of CR3 and CR4 in macrophages and dendritic cells.


Assuntos
Células Dendríticas/imunologia , Inflamação/imunologia , Integrina alfaXbeta2/imunologia , Antígeno de Macrófago 1/imunologia , Macrófagos/imunologia , Podossomos/imunologia , Anticorpos Bloqueadores/imunologia , Antígenos CD18/imunologia , Adesão Celular/imunologia , Adesão Celular/fisiologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Movimento Celular/fisiologia , Células Dendríticas/patologia , Células Dendríticas/fisiologia , Fibrinogênio/imunologia , Humanos , Técnicas In Vitro , Inflamação/patologia , Lipopolissacarídeos/imunologia , Macrófagos/patologia , Macrófagos/fisiologia , Fagocitose/imunologia , Fagocitose/fisiologia , Podossomos/patologia
5.
Mol Immunol ; 123: 40-59, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32413788

RESUMO

Dendritic cells (DCs) are mononuclear phagocytes that are specialized in the induction and functional polarization of effector lymphocytes, thus orchestrating immune defenses against infections and cancer. The population of DC encompasses distinct cell types that vary in their efficacy for complementary functions and are thus likely involved in defending the body against different threats. Plasmacytoid DCs specialize in the production of high levels of the antiviral cytokines type I interferons. Type 1 conventional DCs (cDC1s) excel in the activation of cytotoxic CD8+ T cells (CTLs) which are critical for defense against cancer and infections by intracellular pathogens. Type 2 conventional DCs (cDC2s) prime helper CD4+ T cells for the production of type 2 cytokines underpinning immune defenses against worms or of IL-17 promoting control of infections by extracellular bacteria or fungi. Hence, clinically manipulating the development and functions of DC types could have a major impact for improving treatments against many diseases. However, the rarity and fragility of human DC types is impeding advancement towards this goal. To overcome this roadblock, major efforts are ongoing to generate in vitro large numbers of distinct human DC types. We review here the current state of this research field, emphasizing recent breakthrough and proposing future priorities. We also pinpoint the necessity to develop a consensus nomenclature and rigorous methodologies to ensure proper identification and characterization of human DC types. Finally, we elaborate on how faithful in vitro models of human DC types can accelerate our understanding of the biology of these cells and the engineering of next generation vaccines or immunotherapies against viral infections or cancer.


Assuntos
Células Dendríticas/citologia , Células Dendríticas/fisiologia , Modelos Teóricos , Animais , Apresentação do Antígeno/fisiologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Células Dendríticas/patologia , Humanos , Ativação Linfocitária , Reprodutibilidade dos Testes
6.
Cancer Cell ; 37(5): 655-673.e11, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396861

RESUMO

Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.


Assuntos
Linfócitos B/imunologia , Transformação Celular Neoplásica/imunologia , Reprogramação Celular , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma de Células B/imunologia , Linfoma Folicular/imunologia , Mutação , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Camundongos , Camundongos Endogâmicos C57BL
7.
Crit Rev Oncol Hematol ; 149: 102928, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32234682

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is one rare but clinically aggressive hematological malignancy, and it is typically characterized by skin lesion and bone marrow involvement. Diagnosis of BPDCN relies on the immunophenotype positive for four of CD4, CD56, CD123, TCL1 and BDCA-2, and commonly without the expression of MPO, cytoplasmic CD3, CD13, CD64, cytoplasmic CD79a, CD19 and CD20. Commonly, BPDCN is characterized by high CD123 expression, aberrant NF-κB activation, dependence on TCF4-/BRD4-network, and deregulated cholesterol metabolism. Under conventional therapy, the survival duration is only improved in a small number of BPDCN patients. Therefore, targeted therapy should be developed. Up to now, tagraxofusp is the leading edge and has been approved for BPDCN treatment. However, most of other targeted therapy agents were still not pushed to clinical trials for BPDCN. In this review, we emphatically discuss recent perspectives on BPDCN genetic features and developments of its targeted therapy.


Assuntos
Células Dendríticas/patologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Terapia de Alvo Molecular , Proteínas de Ciclo Celular , Neoplasias Hematológicas/patologia , Humanos , Proteínas Nucleares , Neoplasias Cutâneas , Fatores de Transcrição
8.
Clin Exp Immunol ; 201(1): 1-11, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32278322

RESUMO

Dendritic cells (DCs) are sentinels of the immune system that bridge innate and adaptive immunity. By capturing antigens in peripheral tissue, processing and presenting them with concurrent expression of co-stimulatory molecules and cytokine secretion they control and modulate immune reactions. Through pattern recognition receptors, DCs sense molecules that are associated with infection or tissue damage, frequently resulting in the formation of inflammasomes upon intracellular stimulation. The inherited autoinflammatory familial Mediterranean fever (FMF) is associated with deregulated activity of the pyrin inflammasome leading to acute inflammatory episodes. However, differentiation and function of DCs in this disease are as yet unclear. Therefore, we first determined DC subpopulation frequency in peripheral blood of a cohort of FMF patients. Joint evaluation without classification according to specific patient characteristics, such as mutational status, did not disclose significant differences compared to healthy controls. For the further examination of phenotype and function, we used immature and mature monocyte-derived DCs (imMo-DCs, mMo-DCs) that were generated in vitro from FMF patients. Immunophenotypical analysis of imMo-DCs revealed a significantly elevated expression of CD83, CD86 and human leukocyte antigen D-related (HLA-DR) as well as a significant down-regulation of CD206, CD209 and glycoprotein NMB (GPNMB) in our FMF patient group. Furthermore, FMF imMo-DCs presented a significantly higher capacity to migrate and to stimulate the proliferation of unmatched allogeneic T cells. Finally, the transition towards a more mature, and therefore activated, phenotype was additionally reinforced by the fact that peripheral blood DC populations in FMF patients exhibited significantly increased expression of the co-stimulatory molecule CD86.


Assuntos
Movimento Celular/imunologia , Células Dendríticas/imunologia , Febre Familiar do Mediterrâneo/imunologia , Monócitos/imunologia , Adulto , Antígenos de Diferenciação/imunologia , Células Dendríticas/patologia , Febre Familiar do Mediterrâneo/patologia , Humanos , Masculino , Monócitos/patologia
9.
Nature ; 580(7802): 257-262, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32269339

RESUMO

Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8+ T cells1-3. Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name 'mature DCs enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein-a key checkpoint molecule-in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-γ and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/patologia , Neoplasias Pulmonares/imunologia , Animais , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Humanos , Imunoterapia , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-4/antagonistas & inibidores , Interleucina-4/imunologia , Interleucina-4/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Camundongos , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
10.
Environ Toxicol ; 35(8): 888-894, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32267089

RESUMO

Respiratory syncytial virus (RSV), a member of Paramyxoviridae family is responsible for bronchiolitis and pneumonia. The present study investigated anti-viral and anti-inflammatory activities of jatrophone against RSV-infection in pulmonary epithelial cells in vitro and in mice model in vivo. The changes in viabilities of RSV infected cells by jatrophone treatment were determined by MTT assay. The fluorescence associated with production of ROS was evaluated by fluorescence microscopy using H2DCFDA dye. The IFN-γ secreting cells were detected in mice BALF by stimulation with phorbol myristate acetate and ionomycin. The reduction of BEAS-2B cell viability by RSV was alleviated on treatment with jatrophone in dose based manner. The cytopathogenic changes by RSV infection were prevented and viral growth inhibited by jatrophone in BEAS-2B cells. Jatrophone treatment significantly alleviated RSV mediated overproduction of IL-6/-8 and suppressed ROS generation in the cells. The pulmonary viral titers were found to be markedly lower in mice treated with jatrophone relative to untreated group. The jatrophone treated mice also showed reduced IL-4/-5/-13 levels and elevated IFN-γ level in BALF relative to untreated RSV infected mice. Flow cytometry revealed elevated count of IFN-γ generating cells in RSV infected mice on treatment with jatrophone. Thus jatrophone inhibits viral growth and oxidative damage by RSV in pulmonary epithelial cells. In RSV infected mice jatrophone increased immunity for viral infection by modulating cell phenotype for promotion of anti-viral IFN-γ. Thus jatrophone acts as potential anti-viral compound and may be developed for treatment of respiratory treat infection.


Assuntos
Antivirais/farmacologia , Diterpenos/farmacologia , Interferon gama/metabolismo , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Células Dendríticas/patologia , Modelos Animais de Doenças , Humanos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/patologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/virologia , Carga Viral
11.
An Bras Dermatol ; 95(3): 307-313, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32299739

RESUMO

BACKGROUND: Clinical and histological features may overlap between lichen planopilaris-associated and discoid lupus erythematosus-associated scarring alopecia. OBJECTIVES: The aim of this study was to demonstrate the cutaneous infiltration of plasmacytoid dendritic cells and to compare their distribution pattern in discoid lupus erythematosus and lichen planopilaris. METHODS: Twenty-four cases of discoid lupus erythematosus and 30 cases of lichen planopilaris were examined for immunostaining of the CD123 marker. The percentage and distribution pattern of plasmacytoid dendritic cells and the presence of the plasmacytoid dendritic cells clusters were evaluted in the samples. RESULTS: The number of plasmacytoid dendritic cells was higher in the discoid lupus erythematosus specimens. Aggregations of 10 cells or more (large cluster) were observed in half of the discoid lupus erythematosus specimens and only 2 lichen planopilaris, with 50% sensitivity and 93% specificity for differentiating discoid lupus erythematosus from lichen planopilaris. STUDY LIMITATIONS: Incidence and prevalence of discoid lupus erythematosus-associated scarring alopecia in the scalp are low, so the samples size of our study was small. CONCLUSIONS: We suggest that a plasmacytoid dendritic cells cluster of 10 cells or more is highly specific for distinguishing discoid lupus erythematosus from lichen planopilaris. It also appears that CD123 immunolabeling is valuable in both active and late stages of the disease.


Assuntos
Células Dendríticas/patologia , Subunidade alfa de Receptor de Interleucina-3/imunologia , Líquen Plano/patologia , Lúpus Eritematoso Discoide/patologia , Adulto , Alopecia/patologia , Biomarcadores , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Coloração e Rotulagem
12.
An Bras Dermatol ; 95(2): 144-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32146009

RESUMO

BACKGROUND: Anogenital warts are the leading sexually transmitted infection in patients seeking care at specialized clinics. They may display a vast array of forms, according to the interaction of the virus with the host's immunity. Cellular immunity is the epithelium's main form of defense against the virus, involving an active participation of the Langerhans cells and pro-inflammatory cytokines such as TNF-α. OBJECTIVE: To assess the epithelial immune response of anogenital warts in males, according to the number of lesions presented. METHODS: This is a prospective, cross-sectional study carried out at the dermatology outpatient clinic in a tertiary hospital. We included male patients over 18 years of age without comorbidities who had anogenital condylomata and no previous treatments.In order to evaluate the local epithelial immunity, the lesions were quantified, then removed and employed in CD1a immunohistochemistry assays for assessing the morphometry and morphology of Langerhans cells; TNF-α; reaction was used for determining cytokine positivity in the epithelium. RESULTS: 48 patients were included in the study. There was no statistically significant difference as to the number of Langerhans cells, in their morphology, or the presence of TNF-α. However, patients presenting with more Langerhans cells in the lesions had cells with a star-like and dendritic morphology, whereas in those with a lower cell count had cells with a rounded morphology and no dendrites (p<0.001). STUDY LIMITATIONS: Small number of patients analyzed. CONCLUSION: There was no difference in epithelial immunity between patients having few or many anogenital condyloma lesions as measured by the morphology and morphometry of Langerhans cells and TNF-α; positivity. Such an assessment employing immunity markers differing from the usual ones is expected to yield useful results.


Assuntos
Doenças do Ânus/imunologia , Condiloma Acuminado/imunologia , Doenças dos Genitais Masculinos/imunologia , Células de Langerhans/patologia , Fator de Necrose Tumoral alfa/análise , Doenças do Ânus/patologia , Condiloma Acuminado/patologia , Estudos Transversais , Células Dendríticas/imunologia , Células Dendríticas/patologia , Doenças dos Genitais Masculinos/patologia , Humanos , Imuno-Histoquímica , Células de Langerhans/imunologia , Masculino , Estudos Prospectivos , Valores de Referência , Fator de Necrose Tumoral alfa/imunologia
13.
Cancer Cell ; 37(3): 289-307.e9, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32183949

RESUMO

Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias Pancreáticas/imunologia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Células Dendríticas/patologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia
14.
Vet Res ; 51(1): 33, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131896

RESUMO

Fasciola hepatica has been shown to have a high capacity for immunomodulation of the host response, making the development of protective vaccines extremely difficult. One of these immunomodulation mechanisms is the impairment of dendritic cells (DC) maturation and, therefore, suppression of antigenic presentation. The aim of this study was to evaluate the pathological changes as well as the characterization of two antigen presenting cells, DC (CD1b, CD83 and MHC-II positive) and follicular dendritic cells (FDC) (CNA.42, S100 and CD83 positive) by immunohistochemistry in the hepatic lymph nodes (HLN) and livers of sheep during the early stages of infection with F. hepatica [9 and 18 days post-infection (dpi)], compared with an uninfected group (UC) as a control. The results revealed a marked hyperplasia of HLN germinal centres at 9 and, in particular, 18 dpi, with respect to the UC group, with coincidental increased expression of CNA.42 in FDC of lymphoid follicles and CD1b in the DC of paracortical areas at 18 dpi. However, the expression of MHC-II and CD83 decreased at 9 and, particularly, at 18 dpi in HLN compared with that in the UC group. Since both markers are related to active presentation of antigens by DC and FDC, the results of the present study suggest that, despite the marked hyperplasia of HLN and increase in DC and FDC numbers during early stages of infection, the DC and FDC antigenic presentation capacity, as suggested by the expression of the markers MHC-II and CD83, is suppressed by the parasite. This suppression was not observed in the liver, probably because of the low number of DC. This is the first study of the immunophenotype of DCs and FDC in sheep infected with F. hepatica.


Assuntos
Células Dendríticas Foliculares/patologia , Células Dendríticas/patologia , Fasciolíase/veterinária , Fígado/patologia , Linfonodos/patologia , Doenças dos Ovinos/patologia , Animais , Fasciola hepatica/fisiologia , Fasciolíase/patologia , Marcadores Genéticos , Ovinos
15.
Cancer Res ; 80(10): 1942-1956, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32127354

RESUMO

The recent success of checkpoint blockade therapies has established immunotherapy as one of the most promising treatments for melanoma. Nonetheless, a complete curative response following immunotherapy is observed only in a fraction of patients. To identify what factors limit the efficacy of immunotherapies, we established mouse models that cease to respond to immunotherapies once their tumors exceed a certain stage. Analysis of the immune systems of the organisms revealed that the numbers of tumor-infiltrating dendritic cells (TIDC) drastically decreased with time. Further, in contrast to the current paradigm, once melanoma was established, TIDC did not migrate into sentinel lymph nodes. Instead, they underwent local cell death due to excessive phagocytosis of lysosomes. Importantly, TIDC were required to license the cytotoxic activity of tumor CD8+ T cells, and in their absence, T cells did not lyse melanoma cells. Our results offer a paradigm shift regarding the role of TIDC and a framework to increase the efficacy of immunotherapies. SIGNIFICANCE: This work redefines the role of monocyte-derived dendritic cells in melanoma and provides a novel strategy to increase the efficacy of T-cell-based immunotherapies in nonresponding individuals. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/1942/F1.large.jpg.


Assuntos
Células Dendríticas/patologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Lisossomos , Melanoma/imunologia , Animais , Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunoterapia , Ativação Linfocitária/imunologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL
16.
Sci Adv ; 6(10): eaaz4204, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181368

RESUMO

Currently, there is a huge demand to develop chemoimmunotherapy with reduced systemic toxicity and potent efficacy to combat late-stage cancers with spreading metastases. Here, we report several "cocktail" therapeutic formulations by mixing immunogenic cell death (ICD)-inducing chemotherapeutics and immune adjuvants together with alginate (ALG) for localized chemoimmunotherapy. Immune checkpoint blockade (ICB) antibody may be either included into this cocktail for local injection or used via conventional intravenous injection. After injection of such cocktail into a solid tumor, in-situ gelation of ALG would lead to local retention and sustained release of therapeutics to reduce systemic toxicity. The chemotherapy-induced ICD with the help of immune adjuvant would trigger tumor-specific immune responses, which are further amplified by ICB to elicit potent systemic antitumor immune responses in destructing local tumors, eliminating metastases and inhibiting cancer recurrence. Our strategy of combining clinically used agents for tumor-localized cocktail chemoimmunotherapy possesses great potential for clinical translation.


Assuntos
Anticorpos Neutralizantes/farmacologia , Neoplasias do Colo/terapia , Terapia Combinada/métodos , Doxorrubicina/farmacologia , Neoplasias Mamárias Animais/terapia , Oxaliplatina/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Alginatos/química , Animais , Anticorpos Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Géis , Humanos , Imiquimode/administração & dosagem , Imunoterapia/métodos , Injeções Intralesionais , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Neoplasias Mamárias Animais/imunologia , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
17.
PLoS Pathog ; 16(2): e1008151, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32109259

RESUMO

HIV latency is the major barrier to a cure for people living with HIV (PLWH) on antiretroviral therapy (ART) because the virus persists in long-lived non-proliferating and proliferating latently infected CD4+ T cells. Latently infected CD4+ T cells do not express viral proteins and are therefore not visible to immune mediated clearance. Therefore, identifying interventions that can reverse latency and also enhance immune mediated clearance is of high interest. Interferons (IFNs) have multiple immune enhancing effects and can inhibit HIV replication in activated CD4+ T cells. However, the effects of IFNs on the establishment and reversal of HIV latency is not understood. Using an in vitro model of latency, we demonstrated that plasmacytoid dendritic cells (pDC) inhibit the establishment of HIV latency through secretion of type I IFNα, IFNß and IFNω but not IFNε or type III IFNλ1 and IFNλ3. However, once latency was established, IFNα but no other IFNs were able to efficiently reverse latency in both an in vitro model of latency and CD4+ T cells collected from PLWH on suppressive ART. Binding of IFNα to its receptor expressed on primary CD4+ T cells did not induce activation of the canonical or non-canonical NFκB pathway but did induce phosphorylation of STAT1, 3 and 5 proteins. STAT5 has been previously demonstrated to bind to the HIV long terminal repeat and activate HIV transcription. We demonstrate diverse effects of interferons on HIV latency with type I IFNα; inhibiting the establishment of latency but also reversing HIV latency once latency is established.


Assuntos
Linfócitos T CD4-Positivos , Repetição Terminal Longa de HIV/imunologia , HIV-1/fisiologia , Interferon-alfa/imunologia , Transcrição Genética/imunologia , Latência Viral/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Células HEK293 , Humanos , NF-kappa B/imunologia , Fatores de Transcrição STAT/imunologia
18.
Cell Prolif ; 53(3): e12772, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32003505

RESUMO

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with a high worldwide prevalence and poor prognosis. Researches are urgently needed on its molecular pathogenesis and biological characteristics. Metabolic reprogramming for adaptation to the tumour microenvironment (TME) has been recognized as a hallmark of cancer. Dysregulation of lipid metabolism especially fatty acid (FA) metabolism, which involved in the alternations of the expression and activity of lipid-metabolizing enzymes, is a hotspot in recent study, and it may be involved in HCC development and progression. Meanwhile, immune cells are also known as key players in the HCC microenvironment and show complicated crosstalk with cancer cells. Emerging evidence has shown that the functions of immune cells in TME are closely related to abnormal lipid metabolism. In this review, we summarize the recent findings of lipid metabolic reprogramming in TME and relate these findings to HCC progression. Our understanding of dysregulated lipid metabolism and associated signalling pathways may suggest a novel strategy to treat HCC by reprogramming cell lipid metabolism or modulating TME.


Assuntos
Carcinoma Hepatocelular/metabolismo , Metabolismo dos Lipídeos , Neoplasias Hepáticas/metabolismo , Microambiente Tumoral , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Humanos , Imunidade Celular , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
20.
Neoplasma ; 67(3): 650-659, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32064883

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with aggressive behavior and poor prognosis. We present the first retrospective analysis mapping its incidence and therapeutic outcomes in patients diagnosed and treated from 2000 to 2017 in the Czech Republic. The cohort comprised 14 patients (10 males, 4 females) with a median age at diagnosis of 39 years (range, 5-68 years). Initially, skin involvement was noted in 10 (71%) patients and bone marrow infiltration was present in 9 (64%). The first complete remission was achieved in 6/14 (43%) patients after acute lymphoblastic leukemia/lymphoma induction therapy and in 3/14 (21%) patients after acute myeloid leukemia regimen. Nine patients underwent allogeneic hematopoietic cell transplantation, with two patients achieving the first complete remission only after allogeneic transplantation. Patients undergoing allogeneic hematopoietic cell transplantation had longer overall survival than those treated without transplantation (the median survival over the period 16.4 vs. 8.1 months). Relapse of the disease was a significant predictor of mortality (p=0.05). Over the study period, patients' survival ranged from 3.3 to 44.2 months, with a median overall survival of 13 months. Our results revealed an effectivity of allogeneic hematopoietic cell transplantation on complete remission achievement in refractory/relapsed disease. The study aimed to present the actual data from the Czech Republic and thus contribute to a global understanding of BPDCN.


Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , República Tcheca , Células Dendríticas/patologia , Feminino , Neoplasias Hematológicas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Estudos Retrospectivos , Adulto Jovem
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