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1.
BMC Gastroenterol ; 21(1): 271, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193069

RESUMO

BACKGROUND: γδT cells play an important role in the mucosa inflammation and immunity-associated disorders. Our previous study reported that γδ T cells producing IL-17 were involved in the pathogenesis of post-infectious irritable bowel syndrome (PI-IBS). However, their subset characteristic profile in this kind of disease remains unclear. Thus the current study's aim is to investigate the functionally predominant subset and its role in PI-IBS. METHODS: The total T cells were collected from the peripheral blood of patients with PI-IBS. The peripheral proportion of Vδ1 and Vδ2 subset was detected by FACS after stained with anti δ1-PE and anti δ2-APC. The local colonic proportion of this two subsets were measured under laser confocal fluorescence microscope. Vδ1 γδ T cells were enriched from the total peripheral T cells by minoantibody-immuno-microbeads (MACS) method and cultured, functionally evaluated by CCK-8 assay (proliferation), CD69/CD62L molecules expression assay (activation) and ELISA (IL-17 production) respectively. RESULTS: 1. Vδ1 γδ T cells significantly increased while Vδ2 γδ T cells remained unchanged in both the peripheral blood and local colonic tissue from PI-IBS patients (p < 0.05). 2. When cultured in vitro, the Vδ1 γδ T cells remarkably proliferated, activated and produced IL-17 (p < 0.05). CONCLUSIONS: Our results suggest that Vδ1 γδ T cells was the predominant γδ T cells subset in both peripheral and intestinal tissue, and was the major IL-17 producing γδ T cells in PI-IBS.


Assuntos
Síndrome do Intestino Irritável , Receptores de Antígenos de Linfócitos T gama-delta , Adulto , Humanos , Interleucina-17 , Linfócitos T
3.
Nat Commun ; 12(1): 4098, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215730

RESUMO

Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Biópsia , Estudos de Coortes , Feminino , Humanos , Imunoterapia , Masculino , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida
4.
Nat Commun ; 12(1): 4127, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226552

RESUMO

Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.


Assuntos
Antígenos CD40/imunologia , Glioma/tratamento farmacológico , Estruturas Linfoides Terciárias/imunologia , Animais , Antineoplásicos/farmacologia , Linfócitos B/imunologia , Neoplasias Encefálicas/tratamento farmacológico , Antígeno CD11b , Linhagem Celular Tumoral , Citocinas , Feminino , Expressão Gênica , Glioma/patologia , Humanos , Imunoglobulina G/genética , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Fenótipo , Linfócitos T , Microambiente Tumoral/imunologia
5.
Nat Commun ; 12(1): 4164, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230493

RESUMO

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the ß-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/ß-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/ß-catenin interaction.


Assuntos
GTP Fosfo-Hidrolases/metabolismo , Proteínas de Membrana/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fator 1 de Transcrição de Linfócitos T/metabolismo , Transativadores/metabolismo , beta Catenina/metabolismo , Animais , Transplante de Medula Óssea , Carcinogênese/genética , Modelos Animais de Doenças , Feminino , GTP Fosfo-Hidrolases/genética , Células HEK293 , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas/genética , Fator 1 de Transcrição de Linfócitos T/genética , Linfócitos T/metabolismo , Transativadores/genética , Transcriptoma , beta Catenina/genética
6.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281285

RESUMO

Sjögren's syndrome (SS), a chronic inflammatory disease involving the salivary and lacrimal glands, presents symptoms of sicca as well as systemic manifestations such as fatigue and musculoskeletal pain. Only a few treatments have been successful in management of SS; thus treatment of the disease is challenging. Metformin is the first-line agent for type 2 diabetes and has anti-inflammatory potential. Its immunomodulatory capacity is exerted via activation of 5' adenosine monophosphate-activated protein kinase (AMPK). Metformin inhibits mitochondrial respiratory chain complex I which leads to change in adenosine mono-phosphate (AMP) to adenosine tri-phosphate (ATP) ratio. This results in AMPK activation and causes inhibition of mammalian target of rapamycin (mTOR). mTOR plays an important role in T cell differentiation and mTOR deficient T cells differentiate into regulatory T cells. In this manner, metformin enhances immunoregulatory response in an individual. mTOR is responsible for B cell proliferation and germinal center (GC) differentiation. Thus, reduction of B cell differentiation into antibody-producing plasma cells occurs via downregulation of mTOR. Due to the lack of suggested treatment for SS, metformin has been considered as a treatment strategy and is expected to ameliorate salivary gland function.


Assuntos
Metformina/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Sjogren/etiologia , Síndrome de Sjogren/fisiopatologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Serina-Treonina Quinases TOR/metabolismo
7.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199099

RESUMO

Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP.


Assuntos
Benzoatos/farmacologia , Hidrazinas/farmacologia , Imunomodulação/efeitos dos fármacos , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/metabolismo , Pirazóis/farmacologia , Receptores de Trombopoetina/antagonistas & inibidores , Benzoatos/química , Benzoatos/uso terapêutico , Biomarcadores , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Hidrazinas/química , Hidrazinas/uso terapêutico , Modelos Biológicos , Modelos Moleculares , Terapia de Alvo Molecular/métodos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Receptores de Trombopoetina/química , Receptores de Trombopoetina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
8.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202218

RESUMO

Periprosthetic joint infections (PJIs) caused by Staphylococcus aureus infection are difficult to treat due to antibiotic resistance. It is known that the biofilms from methicillin-resistant S. aureus (MRSA) promote expansion of myeloid-derived suppressor cells (MDSCs) to suppress T-cell proliferation and benefit bacterial infections. This study finds that GMI, a fungal immunomodulatory peptide isolated from Ganoderma microsporum, suppresses MDSC expansion to promote the proliferation of cytotoxic T cells. The enhancement is likely attributed to increased expression of IL-6 and TNF-α and reduction in ROS expression. Similar beneficial effects of GMI on the suppression of MDSC expansion and IL-6 expression are also observed in the whole blood and reduces the accumulation of MDSCs in the infected bone region in a mouse PJI infection model. This study shows that GMI is potentially useful for treating S. aureus-induced PJIs.


Assuntos
Ganoderma/química , Imunomodulação/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Peptídeos/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Artrite Infecciosa/diagnóstico , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/etiologia , Artrite Infecciosa/metabolismo , Biofilmes/efeitos dos fármacos , Biomarcadores , Biópsia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Masculino , Camundongos , Células Supressoras Mieloides/metabolismo , Peptídeos/química , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/etiologia , Infecções Relacionadas à Prótese/metabolismo , Espécies Reativas de Oxigênio , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Linfócitos T/metabolismo
9.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202553

RESUMO

The cells of the immune system, particularly the T lymphocytes, have two main features that distinguish them from the cells of other tissues. They proliferate after activation and have the ability to move in tissues and organs. These characteristics compel them to develop metabolic plasticity in order to fulfil their immune function. This review focuses on the different known mechanisms that allow T cells to adapt their metabolism to the real-life circumstances they operate in, whether it is to exit quiescence, to differentiate into effector cells, or to participate in immune memory formation. Some of the metabolic adaptations to environmental variations that T cells are likely to undergo in their immune monitoring function are also discussed.


Assuntos
Metabolismo Energético , Linfócitos T/metabolismo , Imunidade Adaptativa , Animais , Diferenciação Celular/imunologia , Humanos , Memória Imunológica , Ativação Linfocitária/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
11.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199417

RESUMO

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer treatment. Despite this achievement, mAbs-based therapies are struggling with limitations including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, which prompted a shift towards the development of the small-molecule inhibitors of PD-1/PD-L1 pathways. Even though many small-molecule inhibitors targeting PD-1/PD-L1 interaction have been reported, their development lags behind the corresponding mAb, partly due to the challenges of developing drug-like small molecules. Herein, we report the discovery of a series of novel inhibitors targeting PD-1/PD-L1 interaction via structural simplification strategy by using BMS-1058 as a starting point. Among them, compound A9 stands out as the most promising candidate with excellent PD-L1 inhibitory activity (IC50 = 0.93 nM, LE = 0.43) and high binding affinity to hPD-L1 (KD = 3.64 nM, LE = 0.40). Furthermore, A9 can significantly promote the production of IFN-γ in a dose-dependent manner by rescuing PD-L1 mediated T-cell inhibition in Hep3B/OS-8/hPD-L1 and CD3-positive T cells co-culture assay. Taken together, these results suggest that A9 is a promising inhibitor of PD-1/PD-L1 interaction and is worthy for further study.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/citologia , Antígeno B7-H1/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Interferon gama/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Cultura Primária de Células , Receptor de Morte Celular Programada 1/química , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
12.
Stem Cell Res Ther ; 12(1): 378, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215321

RESUMO

BACKGROUND: Idiopathic pneumonia syndrome (IPS) is a non-infectious fatal complication characterized by a massive infiltration of leukocytes in lungs and diffuse pulmonary injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Conventional immunosuppressive treatments for IPS have poor therapeutic effects. Safe and effective treatments are not yet available and under explorations. Our previous study demonstrated that mesenchymal stem cells (MSCs) can alleviate IPS, but the mechanisms remain unclear. METHODS: Co-cultured pre-activated T cells and MSCs in vitro to observe the changes in the CCR2-CCL2 axis. By establishing an IPS mouse model and administering MSCs to further verify the results of in vitro experiments. RESULTS: Co-culture of pre-activated T cells with MSCs in vitro modulated the CCR2-CCL2 axis, resulting in quiescent T cells and polarization toward CCR2+CD4+ T cell subsets. Blocking CCR2-CCL2 interaction abolished the immunoregulatory effect of MSCs, leading to re-activation of T cells and partial reversion of polarizing toward CCR2+CD4+ T cells. In IPS mouse model, application of MSCs prolonged the survival and reduced the pathological damage and T cell infiltration into lung tissue. Activation of CCR2-CCL2 axis and production of CCR2+CD4+ T cells were observed in the lungs treated with MSCs. The prophylactic effect of MSCs on IPS was significantly attenuated by the administration of CCR2 or CCL2 antagonist in MSC-treated mice. CONCLUSIONS: We demonstrated an important role of CCR2-CCL2 axis in modulating T cell function which is one of the mechanisms of the prophylactic effect of MSCs on IPS.


Assuntos
Células-Tronco Mesenquimais , Pneumonia , Animais , Quimiocina CCL2/genética , Camundongos , Receptores CCR2/genética , Linfócitos T
13.
Stem Cell Res Ther ; 12(1): 374, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215336

RESUMO

Adoptive cell therapy has received a great deal of interest in the treatment of advanced cancers that are resistant to traditional therapy. The tremendous success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells in the treatment of cancer, especially hematological cancers, has exposed CAR's potential. However, the toxicity and significant limitations of CAR-T cell immunotherapy prompted research into other immune cells as potential candidates for CAR engineering. NK cells are a major component of the innate immune system, especially for tumor immunosurveillance. They have a higher propensity for immunotherapy in hematologic malignancies because they can detect and eliminate cancerous cells more effectively. In comparison to CAR-T cells, CAR-NK cells can be prepared from allogeneic donors and are safer with a lower chance of cytokine release syndrome and graft-versus-host disease, as well as being a more efficient antitumor activity with high efficiency for off-the-shelf production. Moreover, CAR-NK cells may be modified to target various antigens while also increasing their expansion and survival in vivo. Extensive preclinical research has shown that NK cells can be effectively engineered to express CARs with substantial cytotoxic activity against both hematological and solid tumors, establishing evidence for potential clinical trials of CAR-NK cells. In this review, we discuss recent advances in CAR-NK cell engineering in a variety of hematological malignancies, as well as the main challenges that influence the outcomes of CAR-NK cell-based tumor immunotherapies.


Assuntos
Neoplasias Hematológicas , Receptores de Antígenos Quiméricos , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia Adotiva , Células Matadoras Naturais , Receptores de Antígenos Quiméricos/genética , Linfócitos T
14.
BMC Infect Dis ; 21(1): 655, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233649

RESUMO

BACKGROUND: Macrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages. METHODS: We applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student's t-test from at least four independent experiments. RESULTS: We validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production. CONCLUSIONS: We have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.


Assuntos
Apoptose/genética , Proteínas de Fluorescência Verde , Infecções por HIV , Macrófagos , RNA Interferente Pequeno , Linfócitos T CD4-Positivos/virologia , Estudo de Associação Genômica Ampla , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Linfócitos T
15.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204767

RESUMO

Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of ß1-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in serum and bronchoalveolar lavage, reticular basement membrane (RBM) thickness and collagen deposits in the mucosa (histology), and airway geometry (CT-imaging) in 92 asthma patients (persistent airflow limitation subtype: n = 47) and 36 controls. Persistent airflow limitation was associated with type-2 inflammation, elevated soluble α2 integrin chain, and changes in the bronchial wall geometry. Both subtypes of asthma showed thicker RBM than control, but collagen deposition and epithelial α1 and α2 integrins staining were similar. Type-I collagen accumulation and RBM thickness were inversely related to the epithelial expression of the α2 integrin chain. Expression of α2ß1 integrin on T-cells and eosinophils was not altered in asthma. Collagen I deposits were, however, more abundant in patients with lower α2ß1 integrin on blood and airway CD8+ T-cells. Thicker airway walls in CT were associated with lower α2 integrin chain on blood CD4+ T-cells and airway eosinophils. Our data suggest that α2ß1 integrin on inflammatory and epithelial cells may protect against airway remodeling advancement in asthma.


Assuntos
Asma/metabolismo , Asma/patologia , Progressão da Doença , Integrina alfa2beta1/metabolismo , Pulmão/patologia , Substâncias Protetoras/metabolismo , Adulto , Idoso , Remodelação das Vias Aéreas , Asma/sangue , Asma/imunologia , Membrana Basal/patologia , Brônquios/diagnóstico por imagem , Brônquios/patologia , Brônquios/fisiopatologia , Lavagem Broncoalveolar , Feminino , Humanos , Inflamação/patologia , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Subunidades Proteicas/metabolismo , Ventilação Pulmonar , Solubilidade , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X
16.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205169

RESUMO

In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer-both in vivo and in vitro clinical trials-has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.


Assuntos
Doenças Autoimunes do Sistema Nervoso/metabolismo , Endocanabinoides/metabolismo , Receptores de Canabinoides/metabolismo , Animais , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Citocinas/metabolismo , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Leucócitos/metabolismo , Receptores de Canabinoides/efeitos dos fármacos , Linfócitos T/metabolismo
17.
Front Immunol ; 12: 697405, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220859

RESUMO

Clinical presentations of COVID-19 are highly variable, yet the precise mechanisms that govern the pathophysiology of different disease courses remain poorly defined. Across the spectrum of disease severity, COVID-19 impairs both innate and adaptive host immune responses by activating innate immune cell recruitment, while resulting in low lymphocyte counts. Recently, several reports have shown that patients with severe COVID-19 exhibit a dysregulated myeloid cell compartment, with increased myeloid-derived suppressor cells (MDSCs) correlating with disease severity. MDSCs, in turn, promote virus survival by suppressing T-cell responses and driving a highly pro-inflammatory state through the secretion of various mediators of immune activation. Here, we summarize the evidence on MDSCs and myeloid cell dysregulation in COVID-19 infection and discuss the potential of MDSCs as biomarkers and therapeutic targets in COVID-19 pneumonia and associated disease.


Assuntos
COVID-19/patologia , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Biomarcadores , Humanos , Inflamação/imunologia , Inflamação/patologia , Índice de Gravidade de Doença
18.
J Chem Phys ; 154(19): 195104, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34240889

RESUMO

Biological processes at the cellular level are stochastic in nature, and the immune response system is no different. Therefore, models that attempt to explain this system need to also incorporate noise or fluctuations that can account for the observed variability. In this work, a stochastic model of the immune response system is presented in terms of the dynamics of T cells and virus particles. Making use of the Green's function and the Wilemski-Fixman approximation, this model is then solved to obtain the analytical expression for the joint probability density function of these variables in the early and late stages of infection. This is then also used to calculate the average level of virus particles in the system. Upon comparing the theoretically predicted average virus levels to those of COVID-19 patients, it is hypothesized that the long-lived dynamics that are characteristics of such viral infections are due to the long range correlations in the temporal fluctuations of the virions. This model, therefore, provides an insight into the effects of noise on viral dynamics.


Assuntos
Imunidade , Modelos Imunológicos , Linfócitos T/imunologia , Linfócitos T/virologia , Vírion/fisiologia , SARS-CoV-2/fisiologia , Processos Estocásticos
19.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203838

RESUMO

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that entails innate and adaptive immune response elements in which PI3K is a potential hub for immune modulation. In a mouse transgenic model with T-cell-specific deletion of p110α catalytic chain (p110α-/-ΔT), we show the modulation of collagen-induced arthritis (CIA) by this isoform of PI3K. In established arthritis, p110α-/-ΔT mice show decreased prevalence of illness than their control siblings, higher IgG1 titers and lower levels of IL-6 in serum, together with decreased ex vivo Collagen II (CII)-induced proliferation, IL-17A secretion and proportion of naive T cells in the lymph nodes. In a pre-arthritis phase, at 13 days post-Ag, T-cell-specific deletion of p110α chain induced an increased, less pathogenic IgG1/IgG2a antibodies ratio; changes in the fraction of naive and effector CD4+ subpopulations; and an increased number of CXCR5+ T cells in the draining lymph nodes of the p110α-/-ΔT mice. Strikingly, T-cell blasts in vitro obtained from non-immunized p110α-/-ΔT mice showed an increased expression of CXCR5, CD44 and ICOS surface markers and defective ICOS-induced signaling towards Akt phosphorylation. These results, plus the accumulation of cells in the lymph nodes in the early phase of the process, could explain the diminished illness incidence and prevalence in the p110α-/-ΔT mice and suggests a modulation of CIA by the p110α catalytic chain of PI3K, opening new avenues of intervention in T-cell-directed therapies to autoimmune diseases.


Assuntos
Artrite Experimental/enzimologia , Artrite Experimental/patologia , Domínio Catalítico , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Linfócitos T/enzimologia , Animais , Anticorpos/sangue , Artrite Experimental/sangue , Artrite Experimental/imunologia , Biomarcadores/metabolismo , Proliferação de Células , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Deleção de Genes , Imunidade , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucina-6/sangue , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Transdução de Sinais
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(8): 679-686, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34236027

RESUMO

Objective To induce the differentiation of hematopoietic stem progenitor cells (HSPCs) into T cell by creating thymic organoids and simulating the three-dimensional structure of thymus tissue in vitro. Methods The retroviral vector expressing the DLL1 and Green fluorescent protein (GFP) was constructed, and the OP9-DLL1 cell line was established in OP9 cells with the aid of retroviral infection. The mRNA and protein level of DLL1 in OP9-DLL1 cells was detected by quantitative real-time PCR and Western blot respectively. Immunofluorescence assay was used to detect the DLL1 protein expression and distribution in OP9-DLL1 cells. HSPCs were extracted from E13.5 fetal liver and bone marrow of C57BL/6 mouse, and mixed with OP9-DLL1 cells in an appropriate ratio respectively, then compacted by centrifuging and cultured at the air-liquid interface in medium. Fluorescence microscope was used to observe the growth of thymic organoids. Flow cytometry was used to detect the expression of T cell surface markers, including CD3, CD4, CD8, CD25, CD44, CD45, CD117 and TCRß. Immunofluorescence cytochemical staining was used to observe the distribution of hematopoietic cells in thymic organoids. Results The retroviral vector expressing DLL1 and GFP was successfully constructed. The OP9 cells were infected with the retrovirus constructed, and OP9-DLL1 cells were obtained by GFP screening. The mRNA and protein level of DLL1 in OP9-DLL1 cells significantly increased, and DLL1 was expressed in the membrane OP9-DLL1 cells. During the 40 days of culture, the thymic organoids remained in good condition and increased gradually in volume. The thymic organoids induced programmed differentiation of T cells, and differentiation of HSPCs into CD3+ T cells. Conclusion OP9-DLL1 cells can be used to construct thymic organoids and to induce differentiation of HSPCs into T cells in vitro.


Assuntos
Células-Tronco Hematopoéticas , Organoides , Animais , Diferenciação Celular , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T , Timo
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