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1.
Nat Commun ; 12(1): 3708, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140506

RESUMO

3D genome alternations can dysregulate gene expression by rewiring enhancer-promoter interactions and lead to diseases. We report integrated analyses of 3D genome alterations and differential gene expressions in 18 newly diagnosed T-lineage acute lymphoblastic leukemia (T-ALL) patients and 4 healthy controls. 3D genome organizations at the levels of compartment, topologically associated domains and loop could hierarchically classify different subtypes of T-ALL according to T cell differentiation trajectory, similar to gene expressions-based classification. Thirty-four previously unrecognized translocations and 44 translocation-mediated neo-loops are mapped by Hi-C analysis. We find that neo-loops formed in the non-coding region of the genome could potentially regulate ectopic expressions of TLX3, TAL2 and HOXA transcription factors via enhancer hijacking. Importantly, both translocation-mediated neo-loops and NUP98-related fusions are associated with HOXA13 ectopic expressions. Patients with HOXA11-A13 expressions, but not other genes in the HOXA cluster, have immature immunophenotype and poor outcomes. Here, we highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.


Assuntos
Cromossomos/metabolismo , Proteínas de Homeodomínio/genética , Leucemia-Linfoma de Células T do Adulto/genética , Conformação Molecular , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Linfócitos T/metabolismo , Translocação Genética , Acetilação , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Criança , Sequenciamento de Cromatina por Imunoprecipitação , Cromossomos/genética , Progressão da Doença , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/genética , Regulação Leucêmica da Expressão Gênica/imunologia , Ontologia Genética , Hematopoese/genética , Histonas/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Imunofenotipagem , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/mortalidade , Leucemia-Linfoma de Células T do Adulto/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico , Linfócitos T/patologia , Adulto Jovem
2.
Nat Commun ; 12(1): 3501, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108465

RESUMO

The characteristics of COVID-19 patients with persistent SARS-CoV-2 infection are not yet well described. Here, we compare the clinical and molecular features of patients with long duration of viral shedding (LDs) with those from patients with short duration patients (SDs), and healthy donors (HDs). We find that several cytokines and chemokines, such as interleukin (IL)-2, tumor necrosis factor (TNF) and lymphotoxin α (LT-α) are present at lower levels in LDs than SDs. Single-cell RNA sequencing shows that natural killer (NK) cells and CD14+ monocytes are reduced, while regulatory T cells are increased in LDs; moreover, T and NK cells in LDs are less activated than in SDs. Importantly, most cells in LDs show reduced expression of ribosomal protein (RP) genes and related pathways, with this inversed correlation between RP levels and infection duration further validated in 103 independent patients. Our results thus indicate that immunosuppression and low RP expression may be related to the persistence of the viral infection in COVID-19 patients.


Assuntos
COVID-19/imunologia , SARS-CoV-2/patogenicidade , Linfócitos B/metabolismo , Linfócitos B/patologia , COVID-19/virologia , Citocinas/sangue , Perfilação da Expressão Gênica , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Leucócitos Mononucleares/patologia , Ativação Linfocitária/genética , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/patologia , Proteínas Ribossômicas/genética , SARS-CoV-2/isolamento & purificação , Transdução de Sinais/genética , Linfócitos T/metabolismo , Linfócitos T/patologia , Eliminação de Partículas Virais
3.
J Clin Neurosci ; 89: 381-388, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34083111

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of extra-nodal non-Hodgkin's lymphoma. Corticosteroids cause transient regression of PCNSL at the radiological and histological level. A growing number of case reports describe histologically confirmed neuroinflammation (sentinel lesions) heralding the development of PCNSL. We present two further cases of sentinel lesions contextualised by a review of past literature. Our aims are to collate existing knowledge on sentinel lesions in PCNSL and explore their pathophysiological significance. Two cases were identified (n = 2) from a cohort of 104 patients with PCNSL referred to a tertiary neurosurgery centre. A literature search identified previously reported cases (n = 14). Median age was 57.5 (range; 26-72); pre-biopsy corticosteroid administration was reported in 50% of cases (n = 8); mean time between biopsies was 10 months (range; 3-60). Common MRI features were homogenous enhancement (10;71.4%) and T2-hyperintensity (11;100%). Histochemical analysis of sentinel lesion biopsy revealed inflammatory CD3/4/5/8-positive T-cells (14; 100%), demyelination (13; 81.3%), rare/scattered CD20-postive B-cells (11;78.6%) and CD68-positive macrophages (10;71.4%). Repeat biopsy confirmed PCNSL in all cases. Waxing and waning CNS inflammation has been identified in 16 patients ultimately diagnosed with PCNSL. Neuro-specialists should be aware of this atypical presentation and maintain a high index of suspicion for lymphoma despite histopathology negative for lymphoma when clinical or radiological features indicate PCNSL.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Linfoma não Hodgkin/patologia , Corticosteroides/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Biópsia , Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Feminino , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/patologia , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiografia , Linfócitos T/metabolismo , Linfócitos T/patologia
4.
Hematol Oncol ; 39 Suppl 1: 15-23, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105821

RESUMO

Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.


Assuntos
Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Dendríticas , Histiocitose de Células de Langerhans , Medicina de Precisão , Linfócitos T , Substituição de Aminoácidos , Diferenciação Celular/genética , Movimento Celular/genética , Células Dendríticas/imunologia , Células Dendríticas/patologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
5.
FASEB J ; 35(6): e21650, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33993539

RESUMO

Mesenchymal stem cells from healthy adipose tissue are adipocytes progenitors with immunosuppressive potential that are used for years in cell therapy. Whether adipose stem cells (ASC) may prevent inflammation in early obesity is not known. To address this question, we performed a kinetic study of high-fat (HF) diet induced obesity in mice to follow the immune regulating functions of adipose stem cells (ASC) isolated from the subcutaneous (SAT) and the visceral adipose tissue (VAT). Our results show that, early in obesity and before inflammation was detected, HF diet durably and differently activated ASC from SAT and VAT. Subcutaneous ASC from HF-fed mice strongly inhibited the proliferation of activated T lymphocytes, whereas visceral ASC selectively inhibited TNFα expression by macrophages and simultaneously released higher concentrations of IL6. These depot specific differences may contribute to the low-grade inflammation that develops with obesity in VAT while inflammation in SAT is delayed. The mechanisms involved differ from those already described for naïve cells activation with inflammatory cytokines and probably engaged metabolic activation. These results evidence that adipose stem cells are metabolic sensors acquiring an obesity-primed immunocompetent state in answer to depot-specific intrinsic features with overnutrition, placing these cells ahead of inflammation in the local dialog with immune cells.


Assuntos
Tecido Adiposo/imunologia , Inflamação/imunologia , Gordura Intra-Abdominal/imunologia , Células-Tronco Mesenquimais/imunologia , Obesidade/fisiopatologia , Gordura Subcutânea/imunologia , Linfócitos T/imunologia , Tecido Adiposo/patologia , Animais , Inflamação/patologia , Gordura Intra-Abdominal/patologia , Ativação Linfocitária , Masculino , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Gordura Subcutânea/patologia , Linfócitos T/patologia
6.
Methods Mol Biol ; 2255: 197-212, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34033105

RESUMO

The rapid, efficient detection of cell death is critical for characterizing the underlying biology of in vitro disease models and, in particular, immunotherapy products used for preclinical therapeutic research. Traditional endpoint assays are laborious to perform for mass screening of therapeutic candidates and may fail to fully capture the kinetics of events surrounding the initiation, duration, and mechanisms of cell death-important events that may affect translational relevance and impact therapeutic decision-making during development. Here, we describe simple, efficient methods to measure apoptosis and immune cell killing in both adherent and nonadherent cell populations using the Incucyte® Live-Cell Analysis system and associated nonperturbing reagents, cells, and protocols. Assays are performed in the user's own incubator with minimal disturbance and may be readily incorporated into existing workflows. Users may multiplex to maximize data collection from each sample. The integrated, user-friendly software does not require advanced technical training, enabling rapid analysis. Taken together, this method provides essential kinetic insight for greater understanding of cell death and the dynamic interactions between immune cells and their targets.


Assuntos
Apoptose , Caspases/metabolismo , Adesão Celular , Processamento de Imagem Assistida por Computador/métodos , Imagem Molecular/métodos , Neoplasias/patologia , Linfócitos T/patologia , Humanos , Cinética , Neoplasias/metabolismo , Linfócitos T/imunologia , Células Tumorais Cultivadas
7.
Laryngoscope ; 131(8): E2452-E2460, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33847388

RESUMO

OBJECTIVES/HYPOTHESIS: Test a new jellyfish collagen biomaterial aimed to increase duration of injection medialization laryngoplasty (IL) against two products in clinical practice. STUDY DESIGN: Animal model. METHODS: Left recurrent laryngeal nerve sectioning and IL were performed in New Zealand White rabbits (N = 6/group). Group 1 received micronized cross-linked jellyfish collagen (MX-JC) and adipose derived stem cells (ADSCs), Group 2, MX-JC alone, Group 3, cross-linked hyaluronic acid (X-HA), and Group 4, micronized acellular dermis (MACD). Animals were sacrificed at 4 and 12 weeks. Major outcomes were MRI tissue volumes and histopathology. RESULTS: After 100 µL IL MRI volumes (means ± STD) at 4 and 12 weeks were: Group 1: 27.2 ± 15.6 and 13.1 ± 5.2 µL, Group 2: 60.8 ± 18 and 27.8 ± 2.47 µL, Group 3: 27.4 ± 12 and 10.6 ± 8 µL, and Group 4: 37.5 ± 11 and 9.85 ± 1 µL. Group 2 volumes were largest and Group 3 were smallest in all comparisons (P < .05). Histologically, low grade inflammatory responses were observed in Group 1, mild histiocytic infiltration in Group 2, widespread muscle fiber loss in Group 3, and plasmocytic infiltration in Group 4. CONCLUSIONS: MX-JC showed the least resorption at 4 and 12 weeks among all groups. T cell inflammatory responses were observed with MX-JC but were reduced by 12 weeks while B cell immune responses, indicative of antibody priming, were predominantly noted with MACD. MX-JC + ADSC showed low grade immunity while the XHA showed greater myocyte loss compared to the other groups. LEVEL OF EVIDENCE: NA Laryngoscope, 131:E2452-E2460, 2021.


Assuntos
Colágeno/farmacologia , Ácido Hialurônico/análogos & derivados , Laringoplastia/métodos , Imageamento por Ressonância Magnética/métodos , Paralisia das Pregas Vocais/terapia , Derme Acelular/efeitos adversos , Animais , Linfócitos B/imunologia , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/farmacologia , Cadáver , Colágeno/administração & dosagem , Modelos Animais de Doenças , Feminino , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/farmacologia , Imunidade/imunologia , Inflamação/patologia , Imageamento por Ressonância Magnética/estatística & dados numéricos , Células-Tronco Mesenquimais/patologia , Plasmócitos/imunologia , Padrões de Prática Médica , Coelhos , Traumatismos do Nervo Laríngeo Recorrente/complicações , Traumatismos do Nervo Laríngeo Recorrente/patologia , Linfócitos T/patologia , Paralisia das Pregas Vocais/diagnóstico , Paralisia das Pregas Vocais/etiologia
8.
Mutat Res ; 865: 503322, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865537

RESUMO

Chronic exposure to benzene is a risk factor for hematological malignancies. Gasoline-station workers are exposed to benzene in gasoline, via both inhalation and dermal contact (attendants and managers) or inhalation (workers in the on-site convenience stores and offices). We have studied the exposure of these workers to benzene and the resulting genotoxic and immunotoxic effects. Levels of urinary trans, trans-muconic acid were higher among gasoline-station workers than among office workers with no known exposure to benzene (comparison group). Among the exposed workers, we observed statistically significant biological effects, including elevated DNA damage (comet assay); higher frequencies of micronuclei and nuclear buds (CBMN assay); lower levels of T-helper lymphocytes and naive Th lymphocytes; lower CD4 / CD8 ratio; and higher levels of NK cells and memory Th lymphocytes. Both groups of exposed workers (inhalation and inhalation + dermal routes) showed similar genotoxic and immunotoxic effects.


Assuntos
Benzeno/toxicidade , Gasolina/toxicidade , Sistema Imunitário/efeitos dos fármacos , Exposição Ocupacional , Adulto , Idoso , Poluentes Ocupacionais do Ar/toxicidade , Brasil/epidemiologia , Ensaio Cometa , Estudos Transversais , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/imunologia , Feminino , Humanos , Sistema Imunitário/metabolismo , Imunomodulação/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Exposição por Inalação/análise , Contagem de Linfócitos , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Testes de Mutagenicidade , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Exposição Ocupacional/estatística & dados numéricos , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Adulto Jovem
9.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925883

RESUMO

Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10-15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to define subgroups of T-ALL has significantly improved in the last few years. The profiling of the gene expression of T-ALL has led to the identification of T-ALL subgroups, and it is important in determining prognostic factors and choosing an appropriate treatment. Novel therapies targeting molecular aberrations offer promise in achieving better first remission with the hope of preventing relapse. The employment of precisely targeted therapeutic approaches is expected to improve the cure of the disease and quality of life of patients. These include therapies that inhibit Notch1 activation (bortezomib), JAK inhibitors in ETP-ALL (ruxolitinib), BCL inhibitors (venetoclax), and anti-CD38 therapy (daratumumab). Chimeric antigen receptor T-cell therapy (CAR-T) is under investigation, but it requires further development and trials. Nelarabine-based regimens remain the standard for treating the relapse of T-ALL.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/uso terapêutico , Bortezomib/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Criança , Perfilação da Expressão Gênica , Terapia Genética , Humanos , Imunoterapia Adotiva , Pediatria , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Intervalo Livre de Progressão , Pirazóis/uso terapêutico , Qualidade de Vida , Recidiva , Sulfonamidas/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/patologia
10.
Life Sci ; 277: 119503, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33865882

RESUMO

Severe coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is characterized by an unpredictable disease course, with variable presentations of different organ systems. The clinical manifestations of COVID-19 are highly variable ranging from mild presentations to severe, life-threatening symptoms and the wide individual variability may be due to the broad heterogeneity in the underlying pathologies. There is no doubt that early management may have a major influence on the outcome. This led the scientists to search for ways to monitor disease progression or to predict outcomes in COVID-19. Although it is not yet possible to predict who will progress to the severe forms or in what time, numerous prospective and longitudinal studies represent the evidence for determining the potential immunological risk factors of COVID-19 critical disease and death. The kinetics and breadth of immune responses during COVID-19 appear to follow a trend which is consistent to the predominant pathological alterations. Recent publications have used these biomarkers to help identify patients who will develop the severe acute COVID-19. Of particular interest is the relationship between the kinetics of peripheral leukocytes and clinical progress of the disease in COVID-19. Although research is ongoing in this area, we present details about the current status of the evaluation. Understanding of the COVID-19 related alterations of the innate and adaptive immune responses may help to promote the vaccine development and immunological interventions.


Assuntos
COVID-19/imunologia , Leucócitos/imunologia , SARS-CoV-2/imunologia , COVID-19/etiologia , COVID-19/patologia , COVID-19/terapia , Progressão da Doença , Humanos , Imunidade Celular , Imunidade Inata , Imunoterapia , Contagem de Leucócitos , Leucócitos/patologia , Macrófagos/imunologia , Macrófagos/patologia , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Linfócitos T/imunologia , Linfócitos T/patologia
11.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807943

RESUMO

We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.


Assuntos
Carcinoma Hepatocelular/radioterapia , Compostos Férricos/farmacologia , Neoplasias Hepáticas/radioterapia , Compostos de Manganês/farmacologia , Nanopartículas/uso terapêutico , Radiação Ionizante , Radiossensibilizantes/farmacologia , Microambiente Tumoral/efeitos da radiação , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Compostos Férricos/química , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Compostos de Manganês/química , Camundongos , Nanopartículas/química , Radiossensibilizantes/química , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800462

RESUMO

Human CD137 (4-1BB), a member of the TNF receptor family, and its ligand CD137L (4-1BBL), are expressed on immune cells and tumor cells. CD137/CD137L interaction mediates bidirectional cellular responses of potential relevance in inflammatory diseases, autoimmunity and oncology. A soluble form of CD137 exists, elevated levels of which have been reported in patients with rheumatoid arthritis and various malignancies. Soluble CD137 (sCD137) is considered to represent a splice variant of CD137. In this report, however, evidence is presented that A Disintegrin and Metalloproteinase (ADAM)10 and potentially also ADAM17 are centrally involved in its generation. Release of sCD137 by transfected cell lines and primary T cells was uniformly inhibitable by ADAM10 inhibition. The shedding function of ADAM10 can be blocked through inhibition of its interaction with surface exposed phosphatidylserine (PS), and this effectively inhibited sCD137 generation. The phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane and thus modifies ADAM10 function. Overexpression of ANO6 increased stimulated shedding, and hyperactive ANO6 led to maximal constitutive shedding of CD137. sCD137 was functionally active and augmented T cell proliferation. Our findings shed new light on the regulation of CD137/CD137L immune responses with potential impact on immunotherapeutic approaches targeting CD137.


Assuntos
Proteína ADAM10/metabolismo , Proteína ADAM17/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Artrite Reumatoide/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Anoctaminas/metabolismo , Artrite Reumatoide/patologia , Membrana Celular/metabolismo , Células HEK293 , Células HT29 , Humanos , Neoplasias/patologia , Proteínas de Transferência de Fosfolipídeos/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologia
13.
BMC Cancer ; 21(1): 429, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33874915

RESUMO

BACKGROUND: Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. RESULTS: We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. CONCLUSION: These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.


Assuntos
Neoplasias/etiologia , Neoplasias/metabolismo , PTEN Fosfo-Hidrolase/deficiência , Linfócitos T/imunologia , Linfócitos T/metabolismo , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Bases de Dados Genéticas , Suscetibilidade a Doenças , Expressão Gênica , Genômica/métodos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Terapia de Alvo Molecular , Neoplasias/patologia , Neoplasias/terapia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Linfócitos T/patologia , Serina-Treonina Quinases TOR/metabolismo , Evasão Tumoral , Microambiente Tumoral
14.
Molecules ; 26(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808813

RESUMO

Positron emission tomography (PET) imaging of activated T-cells with N-(4-[18F]fluorobenzoyl)-interleukin-2 ([18F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [18F]FB-IL-2, which reduces synthesis time and improves radiochemical yield. With this optimized approach, [18F]FB-IL-2 was prepared with a non-decay-corrected radiochemical yield of 3.8 ± 0.7% from [18F]fluoride, 3.8 times higher than previously reported methods. In vitro experiments showed that the radiotracer was stable with good radiochemical purity (>95%), confirmed its identity and showed preferential binding to activated mouse peripheral blood mononuclear cells. Dynamic PET imaging and ex vivo biodistribution studies in naïve Balb/c mice showed organ distribution and kinetics comparable to earlier published data on [18F]FB-IL-2. Significant improvements in the radiochemical manufacture of [18F]FB-IL-2 facilitates access to this promising PET imaging radiopharmaceutical, which may, in turn, provide useful insights into different tumour phenotypes and a greater understanding of the cellular nature and differential immune microenvironments that are critical to understand and develop new treatments for cancers.


Assuntos
Neoplasias do Colo , Interleucina-2 , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Experimentais , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Interleucina-2/química , Interleucina-2/farmacologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Linfócitos T/patologia , Microambiente Tumoral/efeitos dos fármacos
15.
Front Immunol ; 12: 617658, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868232

RESUMO

T cells are essential for eradicating microorganisms and cancer and for tissue repair, have a pro-cognitive role in the brain, and limit Central Nervous System (CNS) inflammation and damage upon injury and infection. However, in aging, chronic infections, acute SARS-CoV-2 infection, cancer, chronic stress, depression and major injury/trauma, T cells are often scarce, exhausted, senescent, impaired/biased and dysfunctional. People with impaired/dysfunctional T cells are at high risk of infections, cancer, other diseases, and eventually mortality, and become multi-level burden on other people, organizations and societies. It is suggested that "Nerve-Driven Immunity" and "Personalized Adoptive Neuro-Immunotherapy" may overcome this problem. Natural Neurotransmitters and Neuropeptides: Glutamate, Dopamine, GnRH-II, CGRP, Neuropeptide Y, Somatostatin and others, bind their well-characterized receptors expressed on the cell surface of naïve/resting T cells and induce multiple direct, beneficial, and therapeutically relevant effects. These Neurotransmitters and Neuropeptides can induce/increase: gene expression, cytokine secretion, integrin-mediated adhesion, chemotactic migration, extravasation, proliferation, and killing of cancer. Moreover, we recently found that some of these Neurotransmitters and Neuropeptides also induce rapid and profound decrease of PD-1 in human T cells. By inducing these beneficial effects in naïve/resting T cells at different times after binding their receptors (i.e. NOT by single effect/mechanism/pathway), these Neurotransmitters and Neuropeptides by themselves can activate, rejuvenate, and improve T cells. "Personalized Adaptive Neuro-Immunotherapy" is a novel method for rejuvenating and improving T cells safely and potently by Neurotransmitters and Neuropeptides, consisting of personalized diagnostic and therapeutic protocols. The patient's scarce and/or dysfunctional T cells are activated ex vivo once by pre-selected Neurotransmitters and/or Neuropeptides, tested, and re-inoculated to the patient's body. Neuro-Immunotherapy can be actionable and repeated whenever needed, and allows other treatments. This adoptive Neuro-Immunotherapy calls for testing its safety and efficacy in clinical trials.


Assuntos
Encéfalo/imunologia , COVID-19/imunologia , Neuropeptídeos/imunologia , Neurotransmissores/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Encéfalo/patologia , Encéfalo/virologia , COVID-19/patologia , Humanos , Rejuvenescimento , Linfócitos T/patologia
16.
J Clin Exp Hematop ; 61(2): 97-101, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33716241

RESUMO

Follicular T-cell lymphoma (FTCL), one of the nodal T-cell lymphomas with T follicular helper (TFH) phenotype, is an uncommon disease. The diagnosis of FTCL is challenging on the distinction from the morphological mimics mostly exemplified by follicular lymphoma. Here, we described a case of FTCL that mimicked lymphocyte-rich classic Hodgkin lymphoma (LRCHL). A 47-year-old male presented with cervical lymphadenopathy. The biopsy specimen demonstrated nodular lymphoid proliferation, which included scattered CD30+ CD15- CD20- PAX5 weakly+ Hodgkin and Reed-Sternberg (HRS)-like cells and a rich distribution of CD3+ CD4+ PD1+ T-cells. Epstein Barr virus was not detected in HRS-like cells, but it was detected in a small proportion of the scattered lymphocytes. The large cells were also negative for programmed cell death ligand 1, which appeared to be coincidental as described in our previous report of LRCHL. However, flow cytometry showed a CD3- CD4+ T-cell population that constituted 37.4% of all gated lymphocytes. A PCR analysis showed a clonal T-cell receptor-gamma gene rearrangement, but not a clonal immunoglobulin heavy chain gene rearrangement, and showed RHOA G17V mutation. The constellation of these findings led us to revise the diagnosis to FTCL. This result indicated that our case belonged to a relatively indolent subgroup of nodal peripheral T-cell lymphoma of TFH phenotype, which affects patients ≤60 years old, recently proposed by our group. This case report expands our understanding of the morphologic spectrum of FTCL and its clinicopathologic significance.


Assuntos
Doença de Hodgkin/diagnóstico , Linfoma Folicular/diagnóstico , Linfoma de Células T/diagnóstico , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia
17.
J Clin Exp Hematop ; 61(2): 61-70, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33716242

RESUMO

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) includes various diseases. Attempts have been made to identify distinct properties of disease within the PTCL, NOS classification and evaluate their significance to prognosis. Comprehensive gene expression analysis and evaluation of genomic abnormalities have successfully identified specific diseases from heterogeneous PTCL, NOS cases. For example, cases with properties of T follicular helper cells have been identified and classified as an entity resembling angioimmunoblastic T-cell lymphoma (AITL), based on both immunohistochemistry and genomic features. Here, we focus on the molecular pathology of PTCL, NOS and discuss recent changes relevant to its classification.


Assuntos
Linfoma de Células T Periférico/diagnóstico , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Linfoma de Células T Periférico/classificação , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Prognóstico , Linfócitos T/patologia
18.
Immunity ; 54(4): 797-814.e6, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33765436

RESUMO

Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.


Assuntos
COVID-19/imunologia , Pulmão/imunologia , Células Mieloides/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , COVID-19/mortalidade , COVID-19/patologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamação , Estudos Longitudinais , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Células Mieloides/patologia , SARS-CoV-2 , Linfócitos T/imunologia , Linfócitos T/patologia , Transcriptoma , Adulto Jovem
19.
Sci Transl Med ; 13(584)2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33649188

RESUMO

Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen-targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies directed against T cell cancers require more selective targeting. Here, we describe an approach to target T cell cancers through T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique TCR ß chain generated from 1 of 30 TCR ß chain variable gene families (TRBV1 to TRBV30). We hypothesized that bispecific antibodies targeting a single TRBV family member expressed in malignant T cells could promote killing of these cancer cells, while preserving healthy T cells that express any of the other 29 possible TRBV family members. We addressed this hypothesis by demonstrating that bispecific antibodies targeting TRBV5-5 (α-V5) or TRBV12 (α-V12) specifically lyse relevant malignant T cell lines and patient-derived T cell leukemias in vitro. Treatment with these antibodies also resulted in major tumor regressions in mouse models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting approach that preserves enough healthy T cells to maintain cellular immunity.


Assuntos
Anticorpos Biespecíficos , Transtornos Linfoproliferativos/terapia , Linfócitos T/patologia , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta
20.
Front Immunol ; 12: 621039, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33659005

RESUMO

The mechanisms that promote local inflammatory injury during lupus nephritis (LN) flare are largely unknown. Understanding the key immune cells that drive intrarenal inflammation will advance our knowledge of disease pathogenesis and inform the development of new therapeutics for LN management. In this study, we analyzed kidney biopsies from patients with proliferative LN and identified a novel inflammatory dendritic cell (infDC) population that is highly expressed in the LN kidney, but minimally present in healthy human kidneys. During an agnostic evaluation of immune transcript expression in the kidneys of patients with proliferative LN, the most abundantly overexpressed transcript from isolated glomeruli was FCER1G, which encodes the Fc receptor gamma chain (FcRγ). To identify the cell types expressing FcRγ that infiltrate the kidney in LN, studies were done on kidney biopsies from patients with active LN using confocal immunofluorescence (IF) microscopy. This showed that FcRγ is abundantly present in the periglomerular (PG) region of the kidney and to a lesser extent in the tubulointerstitium (TI). Further investigation of the surface markers of these cells showed that they were FcRγ+, MHC II+, CD11c+, CD163+, CD5-, DC-SIGN+, CD64+, CD14+, CD16+, SIRPα+, CD206-, CD68-, CD123-, CD3-, and CD11b-, suggesting the cells were infDCs. Quantification of the infDCs showed an average 10-fold higher level of infDCs in the LN kidney compared to the healthy kidneys. Importantly, IF identified CD3+ T cells to be adjacent to these infDCs in the PG space of the LN kidney, whereas both cell types are minimally present in the healthy kidney. Thus, we have identified a previously undescribed DC in lupus kidneys that may interact with intrarenal T cells and play a role in the pathogenesis of kidney injury during LN flare.


Assuntos
Células Dendríticas/imunologia , Rim/metabolismo , Nefrite Lúpica/imunologia , Linfócitos T/metabolismo , Imunidade Adaptativa , Autoimunidade , Biomarcadores/metabolismo , Células Cultivadas , Humanos , Imunofenotipagem , Inflamação , Rim/patologia , Ativação Linfocitária , Receptores Fc/genética , Receptores Fc/metabolismo , Linfócitos T/patologia
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