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1.
J Cell Mol Med ; 25(4): 2279-2284, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33421348

RESUMO

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.


Assuntos
Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Obesidade/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Asma/imunologia , Asma/patologia , Peso Corporal/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Contagem de Linfócito CD4 , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Inflamação , Interleucina-4/antagonistas & inibidores , Interleucina-4/imunologia , Interleucina-4/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Obesidade/imunologia , Obesidade/patologia , Ovalbumina/administração & dosagem , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
2.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33498864

RESUMO

The paracrine and autocrine processes of the host response play an integral role in the success of scaffold-based tissue regeneration. Recently, the immunomodulatory scaffolds have received huge attention for modulating inflammation around the host tissue through releasing anti-inflammatory cytokine. However, controlling the inflammation and providing a sustained release of anti-inflammatory cytokine from the scaffold in the digestive inflammatory environment are predicated upon a comprehensive understanding of three fundamental questions. (1) How does the release rate of cytokine from the scaffold change in the digestive inflammatory environment? (2) Can we prevent the premature scaffold degradation and burst release of the loaded cytokine in the digestive inflammatory environment? (3) How does the scaffold degradation prevention technique affect the immunomodulatory capacity of the scaffold? This study investigated the impacts of the digestive inflammatory environment on scaffold degradation and how pre-mature degradation can be prevented using genipin crosslinking and how genipin crosslinking affects the interleukin-4 (IL-4) release from the scaffold and differentiation of naïve macrophages (M0). Our results demonstrated that the digestive inflammatory environment (DIE) attenuates protein retention within the scaffold. Over 14 days, the encapsulated protein released 46% more in DIE than in phosphate buffer saline (PBS), which was improved through genipin crosslinking. We have identified the 0.5 (w/v) genipin concentration as an optimal concentration for improved IL-4 released from the scaffold, cell viability, mechanical strength, and scaffold porosity, and immunomodulation studies. The IL-4 released from the injectable scaffold could differentiate naïve macrophages to an anti-inflammatory (M2) lineage; however, upon genipin crosslinking, the immunomodulatory capacity of the scaffold diminished significantly, and pro-inflammatory markers were expressed dominantly.


Assuntos
Regeneração Tecidual Guiada/métodos , Imunomodulação , Iridoides/farmacologia , Macrófagos/efeitos dos fármacos , Tecidos Suporte/química , Animais , Diferenciação Celular , Células Cultivadas , Colágeno , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Injeções , Interleucina-4/imunologia , Interleucina-4/metabolismo , Iridoides/uso terapêutico , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Sistema Musculoesquelético/imunologia , Porosidade
3.
Methods Mol Biol ; 2223: 281-293, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226601

RESUMO

Allergic disease is on the rise and yet the underlying cause and risk factors are not fully understood. While lifesaving in many circumstances, the use of antibiotics and the subsequent disruption of the microbiome are positively correlated with the development of allergies. Here, we describe the use of the antibiotic vancomycin in combination with the papain-induced mouse model of allergic disease that allows for the assessment of microbiome perturbations and the impact on allergy development.


Assuntos
Antibacterianos/farmacologia , Asma/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Microbiota/efeitos dos fármacos , Coloração e Rotulagem/métodos , Vancomicina/farmacologia , Animais , Animais Recém-Nascidos , Asma/induzido quimicamente , Asma/genética , Asma/microbiologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Amarelo de Eosina-(YS)/química , Feminino , Hematoxilina/química , Humanos , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Papaína/administração & dosagem , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia
4.
Eur Rev Med Pharmacol Sci ; 24(23): 12536-12544, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336774

RESUMO

OBJECTIVE: We aimed to study the dynamics of cytokines and lymphocyte subsets and their correlation with the prognosis of patients with severe COVID-19. PATIENTS AND METHODS: The lymphocyte subsets and cytokines of 31 patients with severe COVID-19 (7 deaths and 24 survivals) were longitudinally analyzed. RESULTS: The mean age of enrolled patients was 64 years, 24 (77.4%) patients were men, and 23 (74.2%) patients had comorbidities. Compared with survival group, the death group showed significant and sustained increases in the levels of IL-6, IL-8, and IL-10 from baseline to 28 days after admission (all p<0.05). No significant differences were observed in the levels of TNF-α, IL-1b, IL-2, IL-4, IL-5, IL-12P70, IL-17, IFN-α, and IFN-γ between the death group and survival group during the follow-up (all p>0.05). The absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were lower in both survival group and death group patients from hospital admission to 3 days after admission, and gradually recovered in 4 to 35 days in the survival group, but continually stayed at low levels in the death group during the follow-up. CONCLUSIONS: The kinetic changes of cytokines and lymphocyte subsets are related with the prognosis of patients with severe COVID-19.


Assuntos
/imunologia , Citocinas/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , /mortalidade , Feminino , Humanos , Interferon-alfa/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-17/imunologia , Interleucina-1beta/imunologia , Interleucina-2/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Antígenos Comuns de Leucócito/imunologia , Estudos Longitudinais , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologia
5.
Front Immunol ; 11: 574862, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042157

RESUMO

It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Mastócitos/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Edema Pulmonar/imunologia , Trombose/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Influenza Humana/virologia , Interleucina-4/imunologia , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Proto-Oncogênicas c-kit/imunologia , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/virologia , Edema Pulmonar/patologia , Edema Pulmonar/virologia , Trombose/patologia , Trombose/virologia
6.
Cell Mol Immunol ; 17(10): 1092-1094, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32917983
7.
APMIS ; 128(11): 583-592, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32865844

RESUMO

Multiple sclerosis (MS) is an immune-mediated inflammatory disease which affects the central nervous system (CNS). In the present study, the in vivo effects of ATRA, calcitriol, and their combinations on the expression of murine CD4+ T cell cytokines and their specific transcription factors in experimental autoimmune encephalomyelitis (EAE)-induced mice were explored. Thirty-two EAE induced inbred C57BL/6 female mice with an age ranged from 8 to 10 weeks were divided into four categories in a random manner. The first, second, and third groups received ATRA, calcitriol, ATRA+ calcitriol, respectively, and the fourth group received vehicle. The treatment started on the day prior to immunization and through the IP injections every other days for 21 days. The dosages of administration for calcitriol, ATRA, and calcitriol+ ATRA were 100 ng, 250 µg, and 50ng + 125 µg, respectively per mouse. An equal volume of excipient was administered for the vehicle group. T-bet, IFN-γ, GATA-3, and IL-4 genes expression were assessed in the splenocytes of EAE -induced mice. The expression of T-bet and IFN-γ genes in the splenocytes of ATRA, calcitriol and combination- treated mice were significantly reduced compared to vehicle group (p < 0.05). A significant decrease in T-bet expression was observed in the combination-treated group compared to the ATRA-treated group (p < 0.05). The expression of GATA3 and IL-4 genes was significantly increased in the ATRA-, calcitriol-, and combination-treated mice when compared with the control group (p < 0.05). Furthermore, the effect of calcitriol alone and in combination with ATRA was more considerable than that of ATRA alone. The nutraceutical approaches may be promising in the prevention and/or treatment of MS.


Assuntos
Calcitriol/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Tretinoína/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Esquema de Medicação , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia
8.
JAMA Netw Open ; 3(6): e2010895, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492165

RESUMO

Importance: The epidemiologic and clinical characteristics of pediatric patients with coronavirus disease 2019 (COVID-19) have been reported, but information on immune features associated with disease severity is scarce. Objective: To delineate and compare the immunologic features of mild and moderate COVID-19 in pediatric patients. Design, Setting, and Participants: This single-center case series included 157 pediatric patients admitted to Wuhan Children's Hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data were collected from January 25 to April 18, 2020. Exposures: Documented SARS-CoV-2 infection. Main Outcomes and Measures: Clinical and immunologic characteristics were collected and analyzed. Outcomes were observed until April 18, 2020. Results: Of the 157 pediatric patients with COVID-19, 60 (38.2%) had mild clinical type with pneumonia, 88 (56.1%) had moderate cases, 6 (3.8%) had severe cases, and 3 (1.9%) were critically ill. The 148 children with mild or moderate disease had a median (interquartile range [IQR]) age of 84 (18-123) months, and 88 (59.5%) were girls. The most common laboratory abnormalities were increased levels of alanine aminotransferase (ALT) (median [IQR], 16.0 [12.0-26.0] U/L), aspartate aminotransferase (AST) (median [IQR], 30.0 [23.0-41.8] U/L), creatine kinase MB (CK-MB) activity (median [IQR], 24.0 [18.0-34.0] U/L), and lactate dehydrogenase (LDH) (median [IQR], 243.0 [203.0-297.0] U/L), which are associated with liver and myocardial injury. Compared with mild cases, levels of inflammatory cytokines including interleukin 6, tumor necrosis factor α, and interferon γ were unchanged, whereas the level of immune suppressive interleukin 10 was markedly increased in moderate cases compared with mild cases (median [IQR], 3.96 [3.34-5.29] pg/mL vs 3.58 [3.10-4.36] pg/mL; P = .048). There was no statistically significant difference in absolute number of lymphocytes (including T cells and B cells) between mild and moderate cases, but moderate cases were associated with a decrease in neutrophil levels compared with mild cases (median [IQR], 2310/µL [1680/µL-3510/µL] vs 3120/µL [2040/µL-4170/µL]; P = .01). Immunoglobin G and the neutrophil to lymphocyte ratio were negatively associated with biochemical indices related to liver and myocardial injury (immunoglobulin G, ALT: r, -0.3579; AST: r, -0.5280; CK-MB activity: r, -0.4786; LDH: r, -0.4984; and neutrophil to lymphocyte ratio, ALT: r, -0.1893; AST: r, -0.3912; CK-MB activity: r, -0.3428; LDH: r, -0.3234), while counts of lymphocytes, CD4+ T cells, and interleukin 10 showed positive associations (lymphocytes, ALT: r, 0.2055; AST: r, 0.3615; CK-MB activity: r, 0.338; LDH: r, 0.3309; CD4+ T cells, AST: r, 0.4701; CK-MB activity: r, 0.4151; LDH: r, 0.4418; interleukin 10, ALT: r, 0.2595; AST: r, 0.3386; CK-MB activity: r, 0.3948; LDH: r, 0.3794). Conclusions and Relevance: In this case series, systemic inflammation rarely occurred in pediatric patients with COVID-19, in contrast with the lymphopenia and aggravated inflammatory responses frequently observed in adults with COVID-19. Gaining a deeper understanding of the role of neutrophils, CD4+ T cells, and B cells in the pathogenesis of SARS-CoV-2 infection could be important for the clinical management of COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Citocinas/imunologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Distribuição por Idade , Alanina Transaminase/metabolismo , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Aspartato Aminotransferases/metabolismo , Linfócitos B/imunologia , Proteína C-Reativa/imunologia , Linfócitos T CD4-Positivos/imunologia , Criança , Pré-Escolar , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Creatina Quinase Forma MB/metabolismo , Estado Terminal , Feminino , Hospitais Pediátricos , Humanos , Lactente , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-2/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Células Matadoras Naturais/imunologia , L-Lactato Desidrogenase/metabolismo , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Índice de Gravidade de Doença , Distribuição por Sexo , Fator de Necrose Tumoral alfa/imunologia
9.
Am J Med Sci ; 360(2): 137-145, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32423746

RESUMO

BACKGROUND: At present, the effect of operation intervention on pulmonary function is not clear in patients with allergic rhinitis and chronic rhinosinusitis with nasal polyps (AR&CRSwNP). This study was conducted to investigate the effect of vidian neurectomy on pulmonary function and airway hyperresponsiveness (AHR) in patients with AR&CRSwNP. METHODS: The incidences of AHR, bronchial asthma (BA) and pulmonary function impairment in 112 patients with AR&CRSwNP were investigated. Subsequently, we evaluated the outcome of vidian neurectomy and its effect on pulmonary function and AHR. Furthermore, we explored the correlation between postoperative level of eosinophilic cationic protein (ECP) and the changes of pulmonary function indices or dose of methacholine. RESULTS: In this study, the incidences of pulmonary function impairment, bronchial asthma, and AHR in patients with AR&CRSwNP were 61.61%, 69.64%, and 66.96%, respectively. Particularly, vidian neurectomy effectively alleviated nasal symptoms, improved pulmonary function, and reduced AHR in AR&CRSwNP patients. Furthermore, the postoperative level of ECP, IgE, Interleukin-4 and Interleukin-IL-5 was dramatically decreased, and there was an obvious inverse correlation between ECP level and pulmonary function index or dose of methacholine. CONCLUSIONS: Vidian neurectomy is effective in alleviating nasal symptoms, improving pulmonary function, and reducing the risk of AHR of patients with AR&CRSwNP by decreasing the level of ECP.


Assuntos
Denervação/métodos , Gânglio Geniculado/cirurgia , Pólipos Nasais/cirurgia , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Rinite Alérgica/cirurgia , Sinusite/cirurgia , Adulto , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Testes de Provocação Brônquica , Doença Crônica , Proteína Catiônica de Eosinófilo/imunologia , Feminino , Volume Expiratório Forçado , Humanos , Imunoglobulina E/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/imunologia , Pólipos Nasais/fisiopatologia , Complicações Pós-Operatórias/epidemiologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/fisiopatologia , Rinite Alérgica/imunologia , Rinite Alérgica/fisiopatologia , Sinusite/imunologia , Sinusite/fisiopatologia , Resultado do Tratamento , Capacidade Vital
10.
Clin Rev Allergy Immunol ; 59(1): 78-88, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32468411

RESUMO

Coronavirus disease 2019 (COVID-19) is a global pandemic infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and abnormal, overactivated innate immunity and "cytokine storms" have been proposed as potential pathological mechanisms for rapid COVID-19 progression. Theoretically, asthmatic patients should have increased susceptibility and severity for SARS-CoV-2 infection due to a deficient antiviral immune response and the tendency for exacerbation elicited by common respiratory viruses. However, existing studies have not shown an expected prevalence of asthmatic individuals among COVID-19 patients. Certain aspects of type 2 immune response, including type 2 cytokines (IL-4, IL-13, etc.) and accumulation of eosinophils, might provide potential protective effects against COVID-19. Furthermore, conventional therapeutics for asthma, including inhaled corticosteroids, allergen immunotherapy (AIT), and anti-IgE monoclonal antibody, might also reduce the risks of asthmatics suffering infection of the virus through alleviating inflammation or enhancing antiviral defense. The interactions between COVID-19 and asthma deserve further attention and clarification.


Assuntos
Asma/epidemiologia , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Administração por Inalação , Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/imunologia , Asma/terapia , Linfócitos B/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Dessensibilização Imunológica , Progressão da Doença , Eosinófilos/imunologia , Humanos , Interleucina-13/imunologia , Interleucina-4/imunologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Células T Matadoras Naturais/imunologia , Omalizumab/uso terapêutico , Pandemias , Pneumonia Viral/imunologia , Fatores de Proteção , Fatores de Risco , Células Th2/imunologia
11.
Sci Rep ; 10(1): 6754, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317758

RESUMO

Asthma is a heterogeneous disease characterized by chronic inflammation and structural changes in the airways. The airway smooth muscle (ASM) is responsible for airway narrowing and an important source of inflammatory mediators. We and others have previously shown that WNT5A mRNA and protein expression is higher in the ASM of asthmatics compared to healthy controls. Here, we aimed to characterize the functional role of (smooth muscle-derived) WNT5A in asthma. We generated a tet-ON smooth-muscle-specific WNT5A transgenic mouse model, enabling in vivo characterization of smooth-muscle-derived WNT5A in response to ovalbumin. Smooth muscle specific WNT5A overexpression showed a clear trend towards enhanced actin (α-SMA) expression in the ASM in ovalbumin challenged animals, but had no effect on collagen content. WNT5A overexpression in ASM also significantly enhanced the production of the Th2-cytokines IL4 and IL5 in lung tissue after ovalbumin exposure. In line with this, WNT5A increased mucus production, and enhanced eosinophilic infiltration and serum IgE production in ovalbumin-treated animals. In addition, CD4+ T cells of asthma patients and healthy controls were stimulated with WNT5A and changes in gene transcription assessed by RNA-seq. WNT5A promoted expression of 234 genes in human CD4+ T cells, among which the Th2 cytokine IL31 was among the top 5 upregulated genes. IL31 was also upregulated in response to smooth muscle-specific WNT5A overexpression in the mouse. In conclusion, smooth-muscle derived WNT5A augments Th2 type inflammation and remodelling. Our findings imply a pro-inflammatory role for smooth muscle-derived WNT5A in asthma, resulting in increased airway wall inflammation and remodelling.


Assuntos
Remodelação das Vias Aéreas/imunologia , Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Pulmão/imunologia , Músculo Liso/imunologia , Proteína Wnt-5a/imunologia , Actinas/genética , Actinas/imunologia , Remodelação das Vias Aéreas/genética , Alérgenos/administração & dosagem , Animais , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Movimento Celular , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunoglobulina E/biossíntese , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Interleucinas/genética , Interleucinas/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Músculo Liso/química , Músculo Liso/patologia , Ovalbumina/administração & dosagem , Cultura Primária de Células , Transgenes , Proteína Wnt-5a/genética , Proteína Wnt-5a/farmacologia
12.
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
13.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L888-L899, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32130032

RESUMO

We have previously demonstrated that upregulation of Sonic hedgehog (SHH) expression in allergic airway epithelia essentially contributes to the goblet cell metaplasia and mucous hypersecretion. However, the mechanism underlying the upregulation of SHH expression remains completely unknown. In cultured human airway epithelial cells, IL-4/IL-13 but not IL-5 robustly induces the mRNA and protein expression of SHH and in turn activates SHH signaling by promoting the JAK/STAT6-controlling transcription of SHH gene. Moreover, intratracheal instillation of IL-4 and/or IL-13 robustly activates STAT6 and concomitantly upregulates SHH expression in mouse airway epithelia, whereas, in Club cell 10-kDa protein (CC10)-positive airway epithelial cells of children with asthma, activated STAT6 closely correlates with the increased expression of SHH and high activity of SHH signaling. Finally, intratracheal inhibition of STAT6 by AS-1517499 significantly diminished the allergen-induced upregulation of SHH expression, goblet cell phenotypes, and airway hyperresponsiveness, in an ovalbumin- or house dust mite-induced mouse model with allergic airway inflammation,. Together, upregulation of SHH expression by IL-4/IL-13-induced JAK/STAT6 signaling contributes to allergic airway epithelial remodeling, and this study thus provides insight into how morphogen signaling is coordinated with Th2 cytokine pathways to regulate tissue remodeling in chronic airway diseases.


Assuntos
Asma/genética , Proteínas Hedgehog/genética , Interleucina-13/genética , Interleucina-4/genética , Mucosa Respiratória/imunologia , Animais , Antiasmáticos/farmacologia , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/patologia , Linhagem Celular , Criança , Feminino , Regulação da Expressão Gênica , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/imunologia , Células Caliciformes/patologia , Proteínas Hedgehog/imunologia , Humanos , Interleucina-13/imunologia , Interleucina-13/farmacologia , Interleucina-4/imunologia , Interleucina-4/farmacologia , Interleucina-5/genética , Interleucina-5/imunologia , Janus Quinases/genética , Janus Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Cultura Primária de Células , Pirimidinas/farmacologia , Pyroglyphidae/química , Pyroglyphidae/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Fator de Transcrição STAT6/antagonistas & inibidores , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Transcrição Genética , Uteroglobina/genética , Uteroglobina/imunologia
14.
Microb Cell Fact ; 19(1): 53, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32122351

RESUMO

BACKGROUND: Existing methods for preparing influenza vaccines pose the greatest challenge against highly pandemic avian influenza H7N9 outbreak in the poultry and humans. Exploring a new strategy for manufacturing and delivering a safe and effective H7N9 vaccine is needed urgently. RESULTS: An alternative approach is to develop an influenza H7N9 oral vaccine based on yeast display technology in a timely manner. Hemagglutinin (HA) of A/Anhui/1/2013 (AH-H7N9) is used as a model antigen and characterized its expression on the surface of Saccharomyces cerevisiae (S.cerevisiae) EBY 100. Mice administrated orally with S.cerevisiae EBY100/pYD5-HA produced significant titers of IgG antibody as well as significant amounts of cytokines IFN-γ and IL-4. Importantly, S.cerevisiae EBY100/pYD5-HA could provide effective immune protection against homologous A/Anhui/1/2013 (AH-H7N9) virus challenge. CONCLUSIONS: Our findings suggest that platform based on yeast surface technology provides an alternative approach to prepare a promising influenza H7N9 oral vaccine candidate that can significantly shorten the preparedness period and result in effective protection against influenza A pandemic.


Assuntos
Anticorpos Antivirais/sangue , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Administração Oral , Animais , Técnicas de Visualização da Superfície Celular , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Imunoglobulina G/sangue , Subtipo H7N9 do Vírus da Influenza A , Interferon gama/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia , Saccharomyces cerevisiae
15.
Comp Immunol Microbiol Infect Dis ; 70: 101469, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32199179

RESUMO

INTRODUCTION: Cystic echinococcosis (CE) is a chronic zoonotic disease caused by the larval stage of Echinococcus granulosus (E. granulosus), which affects domestic and wild carnivores as the definitive host and ungulates as intermediate hosts. In intermediate hosts, both Th1 and Th2 cells are involved in the immune responses to an echinoccocal infection. This study aimed to investigate production of IL-4, IL-10, and IFN-γ cytokines in peripheral blood mononuclear cells (PBMCs) of CE patients before and after surgical treatment. METHODS: To evaluate cytokine production in response to E. granulosus antigens, we investigated IL-4, IL-10, and IFN-γ production in PBMCs of 20 CE patients in response to hydatid cyst fluid antigen (HCF-Ag) before and after surgical treatment using ELISA. RESULTS: The mean IL-4 production from HCF-Ag stimulated PBMCs was significantly decreased (p < 0.05), while IFN-γ was significantly increased in HCF-Ag stimulated PBMCs in patients after surgery (p = 0.005). Furthermore, our results showed that there is no significant difference between IL-10 production in patients before and after treatment (p = 0.562). CONCLUSIONS: Our data Indicated production of IL-4 in cultured PBMCs of CE patients stimulated with HCF-Ag was decreased significantly. While, production of IFN-γ was increased significantly in responses to HCF Ag after surgery. We concluded that the evaluation of IL-4 and IFN-γ in HCF-Ag stimulated PBMCs of CE patients should be considered as a useful marker in the follow up of patients with cystic echinococcosis.


Assuntos
Citocinas/imunologia , Equinococose/imunologia , Leucócitos Mononucleares/imunologia , Adolescente , Adulto , Idoso , Animais , Antígenos de Helmintos/farmacologia , Células Cultivadas , Equinococose/cirurgia , Echinococcus granulosus , Feminino , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Irã (Geográfico) , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th2/imunologia , Adulto Jovem
16.
J Immunol Methods ; 478: 112721, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32033786

RESUMO

In vitro models of differing macrophage functions are useful since human monocyte-derived macrophages are short-lived, finite and vary from donor to donor. Published protocols using the promonocytic cell line THP-1 have tended to result in cells that closely resemble classically-activated macrophages, differentiated in IFNγ and LPS. However, no protocol, to date, has fully recapitulated polarization of THP-1 to the M(IL-4) or M(IL-10) macrophage phenotypes seen when human monocyte-derived macrophages are exposed to each cytokine. Here we present protocols that can be used to prepare M(IL-4) polarized THP-1 that transcribe CCL17, CCL26, CD200R and MRC1 and M(IL-10) cells which transcribe CD163, C1QA and SEPP1. We show that the inhibitory Fcγ Receptor IIb is preferentially expressed on the surface of M(IL-4) cells, altering the balance of activating to inhibitory Fcγ Receptors. Adoption of standardized experimental conditions for macrophage polarization will make it easier to compare downstream effector functions of different macrophage polarization states, where the impact of PMA exposure is minimized and rest periods and cytokine exposure have been optimized.


Assuntos
Técnicas de Cultura de Células/métodos , Macrófagos/imunologia , Técnicas de Cultura de Células/normas , Diferenciação Celular/imunologia , Meios de Cultura , Humanos , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/metabolismo , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Células THP-1
17.
Immunology ; 159(4): 441-449, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31957000

RESUMO

Signaling by Kit has been extensively studied in hematopoietic cells and is essential for the survival, proliferation and maintenance of hematopoietic stem and progenitor cells. In addition to the activation of intrinsic signaling pathways, Kit has been shown to interact with lineage-restricted type I cytokine receptors and produce cross signals, e.g. erythropoietin receptor, interleukin-7 receptor (IL-7R), IL-3R. Based on the earlier studies, we hypothesize that Kit activate other type I cytokine receptors in a cell-specific manner and execute cell-specific function. To investigate other Kit-activated receptors, we tested Kit and IL-4R cross-receptor activation in murine bone-marrow-derived mast cells, which express both Kit and IL-4R at the surface level. Kit upon activation by Kit ligand (KL), activated IL-4Rα, γC , and signal transducer and activator of transcription 6 independent of its cognate ligand IL-4. Though KL and IL-4 are individually mitogenic, combinations of KL and IL-4 synergistically promoted mast cell proliferation. Furthermore, inhibition of lipid raft formation by methyl-ß-cyclodextrin resulted in loss of synergistic proliferation. Together the data suggest IL-4R as a novel Kit-activated receptor. Such cross-receptor activations are likely to be a universal mechanism of Kit signaling in hematopoiesis.


Assuntos
Interleucina-4/farmacologia , Mastócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/genética , Receptores de Interleucina-4/genética , Fator de Transcrição STAT6/genética , Fator de Células-Tronco/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Hematopoese/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Mastócitos/citologia , Mastócitos/imunologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-kit/imunologia , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/imunologia , Receptores de Interleucina-3/genética , Receptores de Interleucina-3/imunologia , Receptores de Interleucina-4/imunologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Fator de Células-Tronco/genética , Fator de Células-Tronco/imunologia , beta-Ciclodextrinas/farmacologia
18.
J Immunol ; 204(4): 819-831, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31900339

RESUMO

IL-3, a cytokine secreted by activated T lymphocytes, is known to regulate the proliferation, survival, and differentiation of hematopoietic cells. However, the role of IL-3 in regulation of T cell functions is not fully delineated. Previously, we have reported that IL-3 plays an important role in development of regulatory T cells in mice. In this study, we investigated the regulation of IL-3R expression on human Th cells and also examined the role of IL-3 in effector functions of these cells. We found that human peripheral blood Th cells in resting state do not show surface expression of IL-3R; however, its expression was observed at transcript and intracellular protein levels. The functional IL-3R expression on the surface was seen only after antigenic stimulation. When naive Th cells were activated in the presence of various cytokines, we found that IL-4 significantly increases the surface expression of IL-3R and also increases the number of IL-3R+ Th cells. Interestingly, IL-3R+ cells exhibit a Th2 cell-like phenotype and show high GATA-3 expression. Moreover, Th2 cells in presence of IL-3 show increased expression of type 2 effector cytokines, such as IL-4, IL-5, and IL-13. Furthermore, IL-3R expressing and IL-3-secreting Th cells were high in house dust mite-allergic patients. Thus, to our knowledge, we provide the first evidence that the expression of IL-3R on activated human Th cells is modulated by IL-4, and IL-3 regulates the effector functions of Th2 cells. Our results suggest that IL-3 may play an important role in regulating allergic immune responses.


Assuntos
Diferenciação Celular/imunologia , Interleucina-3/imunologia , Interleucina-4/imunologia , Receptores de Interleucina-3/imunologia , Células Th2/imunologia , Humanos , Hipersensibilidade/imunologia , Interleucina-3/metabolismo , Interleucina-4/metabolismo , Ativação Linfocitária/imunologia , Receptores de Interleucina-3/metabolismo
19.
J Allergy Clin Immunol ; 145(3): 808-817.e2, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31805312

RESUMO

BACKGROUND: Specific inflammatory pathways are indicated to contribute to severe asthma, but their individual involvement in the development of airway hyperresponsiveness remains unexplored. OBJECTIVE: This experimental study in human small bronchi aimed to provide insight into which of the type 2 and type 17 cytokines cause hyperresponsiveness of airway smooth muscle. METHODS: Explanted small bronchi isolated from human lung tissue and human airway smooth muscle cells were treated for 2 and 1 day(s), respectively, with 100 ng/mL of IL-4, IL-5, IL-13, or IL-17A, and contractile responses, Ca2+ mobilization, and receptor expression were assessed. RESULTS: Treatment with IL-13 increased the potency of histamine, carbachol, and leukotriene D4 as contractile agonists. IL-4, but not IL-5 or IL-17A, also increased the potency of histamine. In human airway smooth muscle cells, IL-13 and IL-4, but not IL-5 and IL-17A, enhanced the histamine-induced Ca2+ mobilization that was accompanied with increased mRNA expression of histamine H1 and cysteinyl leukotriene CysLT1 receptors. RNA sequencing of isolated bronchi confirmed the IL-13-mediated upregulation of H1 and CysLT1 receptors, without showing an alteration of muscarinic M3 receptors. Dexamethasone had no effects on IL-13-induced hyperresponsiveness in human bronchi, the increased Ca2+ mobilization, or the enhanced receptor expression. In contrast, antagonism of the common receptor for IL-13 and IL-4 by the biologic dupilumab prevented the effects of both IL-13 and IL-4 in human bronchi and human airway smooth muscle cells. CONCLUSIONS: The glucocorticoid-insensitive hyperrresponsiveness in isolated human airways induced by IL-13 and IL-4 provides further evidence that the IL-4Rα pathway should be targeted as a new strategy for the treatment of airway hyperresponsiveness in asthma.


Assuntos
Asma , Bronquíolos/efeitos dos fármacos , Interleucina-13/farmacologia , Interleucina-4/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/imunologia , Asma/metabolismo , Bronquíolos/imunologia , Feminino , Humanos , Interleucina-13/imunologia , Interleucina-17/imunologia , Interleucina-17/farmacologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Interleucina-5/farmacologia , Masculino , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Técnicas de Cultura de Órgãos
20.
Immunopharmacol Immunotoxicol ; 42(1): 22-27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31856612

RESUMO

Aim: Rheumatoid arthritis (RA) is a prevalent inflammatory, autoimmune diseases characterized by inflammation and destruction of joints. Disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs can have modulatory interference in disease process. In this study, the effect of Guluronic Acid (G2013) as a novel non-steroidal anti-inflammatory drug (NSAID) with immunomodulatory effects was evaluated on IL-17, RORγt, IL-4 and GATA-3 gene expression in RA patients.Methods: Fourteen patients with RA who had an inadequate response to conventional treatments were included in this clinical trial. During this trial, patients were permitted to continue the conventional therapy excluding NSAIDs. G2013 was administered orally at dose of 500 mg twice daily for 12 weeks. The peripheral blood mononuclear cells (PBMCs) were collected before and after treatment to evaluate the gene expression levels of IL-4, GATA-3, IL-17 and RORγt.Results: Primary and secondary efficacy endpoints and Disease Activity Score (DAS) 28 showed an improvement after 12 weeks of treatment. G2013 has a potent efficacy on gene expression of these molecules, so that it could decrease IL-17 and RORγt levels and increase IL-4 and GATA-3 levels after 12 weeks of treatment. Reduction of IL-17 was statistically non-significant whereas for its transcription factor (RORγt) was statistically significant. Moreover, the gene expression results were in accordance with the clinical and preclinical assessments.Conclusion: G2013 as a natural novel drug showed a significant increase on IL-4 and GATA-3 and a significant decrease on RORγt gene expression after 12 weeks oral administration of this drug in RA patients. (Clinical trial identifier: IRCT2016092813739N5).


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Reumatoide , Fator de Transcrição GATA3/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácidos Hexurônicos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Interleucina-17/imunologia , Interleucina-4/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Adulto , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
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