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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 865-870, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33148379

RESUMO

Objective To investigate dynamic changes of type 3 innate lymphoid cells (ILC3) in lungs of mice with bronchopulmonary dysplasia (BPD). Methods Forty newborn C57BL/6 mice were randomized into air group and the hyperoxia group, 20 mice in each group. C57BL/6 newborn mice were delivered by caesarean section on the 19th day of pregnancy and exposed to 850 mL/L O2 for replication of the BPD model. Five mice in each group were sacrificed 1 day, 3, 7, 14 days after they were born for procurement of fresh lung tissues. HE staining was used to observe the pathological changes of lung tissues. ELISA was used to detect the protein content of downstream cytokines interleukin-17 (IL-17), IL-22 and granulocyte-macrophage colony stimulating factor (GM-CSF) in lung homogenate. Flow cytometry was used for measuring the proportion of ILC3 in lymphocytes as well as the proportions of IL-17+ ILC3 and IL-22+ ILC3 in the lung. Results The proportion of ILC3 in lung tissues reached the peak on the 7th day after birth. In contrast with the air group, the proportion of ILC3 in the hyperoxia group was significantly elevated at the same time points. The protein content of IL-17 and IL-22 in the hyperoxia group went up significantly in comparison with those in the air group at the same time points, while the GM-CSF content in the hyperoxia group showed no significant changes. The proportions of IL-17+ILC3 and IL-22+ILC3 in the hyperoxia group significantly increased as compared with those in the air group at the same time points. Conclusion The secretion of IL-17 and IL-22 derived from ILC3 is associated with BPD.


Assuntos
Displasia Broncopulmonar/imunologia , Interleucina-17/imunologia , Interleucinas/imunologia , Linfócitos/citologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Hiperóxia , Imunidade Inata , Pulmão/citologia , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Distribuição Aleatória
2.
Medicine (Baltimore) ; 99(45): e23068, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157966

RESUMO

BACKGROUND: Generalized pustular psoriasis (GPP) is a systemic inflammatory disease with poor outcomes, and several studies have suggested that the mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to GPP, where the polymorphism c.115+6T>C is reported to be the most common mutation of IL36RN. This study was performed to clarify and comprehensively evaluate the relationship between IL36RN gene polymorphism and the susceptibility of GPP subtypes. METHODS: To conduct a thorough literature review, studies were obtained using databases such as Pubmed, EMBASE, Cochrane, China National Knowledge Infrastructure, and the Wanfang database. Only studies published up to December 2019 were included. The quality of the research studies was estimated using the Newcastle-Ottawa scale. The total odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were pooled and analysed using STATA 14. The publication bias was evaluated through the Egger test, performed using the aforementioned software. Five common gene models were built and analysed to assess the association between the polymorphism c.115+6T>C and subtypes of GPP. RESULTS: A total of 10 studies were selected, including 683 cases of GPP patients. Meta-analyses showed that there was a significant statistical correlation of IL36RN mutation between GPP with or without psoriasis vulgaris (OR = 3.82, 95%CI 2.63-5.56) and between adult GPP and paediatric GPP (OR = 0.42, 95%CI 0.23-0.77). No obvious discrepancy between European patients (OR = 4.03, 95%CI 2.23-7.26) and Asian patients was found. The gene models showed clear associations between the polymorphism c.115+6T>C and GPP through the dominant model (CC+ TC vs TT, OR 2.74, 95%CI 2.06-3.64), recessive model (CC vs CT + TT, OR 4.33, 95%CI 2.84-6.60), homozygote model (CC vs TT, OR 4.37, 95%CI 2.88-6.62), heterozygote model (CT vs TT, OR 2.26, 95%CI 1.32-3.85) and allelic model (C vs T, OR 3.35, 95%CI 2.63-4.27). CONCLUSION: The IL36RN mutation is strongly related to GPP without psoriasis vulgaris and the early onset of GPP. Furthermore, the single-nucleotide polymorphism c.115+6T>C of the IL36RN gene plays a significant role in GPP vulnerability, especially in homozygous mutation. GPP could be a different inflammatory disease, independent of psoriasis.


Assuntos
Predisposição Genética para Doença/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único/genética , Psoríase/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , China/epidemiologia , Gerenciamento de Dados , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/etnologia , Heterozigoto , Homozigoto , Humanos , Mutação/genética , Psoríase/microbiologia , Psoríase/patologia , Adulto Jovem
3.
Trials ; 21(1): 876, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092653

RESUMO

OBJECTIVES: To investigates the effectiveness of curcumin-containing Nanomicelles as a therapeutic supplement in the treatment of patients with COVID-19 and its effect on immune responses balance changes following treatment. TRIAL DESIGN: This study is conducted as a prospective, placebo-controlled with parallel group, single-center randomized clinical trial on COVID-19 patients. PARTICIPANTS: Patients are selected from the COVID-19 ward of Shahid Mohammadi Hospital in Bandar Abbas, Iran. INCLUSION CRITERIA: 1. Real time PCR-approved positive COVID-19 test. 2. Both gender 3. Age between 18 and 75 years 4. Signing a written consent 5. Lack of participation in other clinical trials Exclusion criteria: 1. Pregnancy or lactation 2. Allergy to turmeric or curcumin 3. Smoking 4. Patient connected to the ventilator 5. SaO2 less than 90% or PaO2 less than 8 kPa 6. Having comorbidities (such as severe renal failure, Glomerular filtration rate less than 30 ml/min, liver failure, Congestive heart failure, or Chronic obstructive pulmonary disease) 7. History of gallstones 8. History of gastritis or active gastrointestinal ulcer INTERVENTION AND COMPARATOR: In addition to the routine standard treatments for COVID-19, in the intervention group, 40mg nanomicelles containing curcumin (SinaCurcumin Capsule, Exir Nano Sina Company, Iran), four times per day (after breakfast, lunch, dinner and before bedtime) and in the placebo group as the control group, capsules with the same appearance and characteristics (Placebo capsules, Exir Nano Sina Company, Iran) are prescribed for two weeks. MAIN OUTCOMES: The effectiveness of Nano micelles containing curcumin treatment will be evaluated as daily clinical examinations of patients in both groups and, on days 0, 7 and 14, complete clinical symptoms and laboratory findings including peripheral blood and serum parameters such as inflammatory markers will be measured and recorded. Moreover, in order to evaluate the balance of immune responses changes following treatments, serum level of IFN-γ, IL-17, Il-4 and TGF-ß serum cytokines will be measured in both groups at time points of 0, 7 and 14 days post treatment. Gene expression of t-bet, GATA-3, FoxP3 and ROR- γT will also be measured at mentioned time points to assess the shift of T helper1, T helper2, T regulatory and T helper 17 immune responses following treatment. RANDOMISATION: Randomized trials will be performed on 40 COVID-19 patients which will be randomized using encoded sealed boxes with computer generated random digits with 1:1 allocation ratio. In order to randomization, placebo and SinaCurcumin Capsules will be numbered first by computer generated random digits. SinaCurcumin and placebo will then be stored and numbered in sealed packages based on generated random numbers. Finally, according to the order in which patients enter the study, packages are given to patients based on their number. BLINDING (MASKING): The present study will be blind for all patients, physicians and nurses, laboratory technicians and statisticians. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 40 patients will be included in the study, 20 of them will be randomly assigned to the intervention group and 20 to the placebo group. TRIAL STATUS: This is Version 1.0 of protocol dated 21 May 2020. The recruitment was started June 24, 2020 and is expected to be completed by October 31, 2020. TRIAL REGISTRATION: This present clinical trial has been registered in the Iranian Registry of Clinical Trials (IRCT) with the registration code of "IRCT20200611047735N1", https://www.irct.ir/trial/48843 . Dated: 19 June 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus/efeitos dos fármacos , Corantes/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Curcumina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adolescente , Adulto , Idoso , Betacoronavirus/genética , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Corantes/efeitos adversos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Curcumina/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Feminino , Expressão Gênica/genética , Humanos , Interleucinas/imunologia , Irã (Geográfico)/epidemiologia , Masculino , Micelas , Pessoa de Meia-Idade , Pandemias , Placebos/administração & dosagem , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
4.
Blood Adv ; 4(20): 5035-5039, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33075136

RESUMO

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-driven coronavirus disease 2019 (COVID-19) has caused unprecedented human death and has seriously threatened the global economy. Early data suggest a surge in proinflammatory cytokines in patients with severe COVID-19, which has been associated with poor outcomes. We recently postulated that the inflammatory response in patients with severe COVID-19 disease is not inhibited by natural killer (NK) cells, resulting in a "cytokine storm." Here, we assessed the NK-cell functional activity and the associated cytokines and soluble mediators in hospitalized COVID-19 patients. Significantly impaired NK-cell counts and cytolytic activity were observed in COVID-19 patients when compared with healthy controls. Also, cytokines like interleukin 12 (IL12), IL15, and IL21 that are important for NK-cell activity were not detected systematically. Serum concentrations of soluble CD25 (sCD25)/soluble IL2 receptor α (sIL2-Rα) were significantly elevated and were inversely correlated with the percentage of NK cells. Impaired NK-cell cytolytic activity together with other laboratory trends including elevated sCD25 were consistent with a hyperinflammatory state in keeping with macrophage-activation syndrome. Our findings suggest that impaired counts and cytolytic activity of NK cells are important characteristics of severe COVID-19 and can potentially facilitate strategies for immunomodulatory therapies.


Assuntos
Infecções por Coronavirus/imunologia , Citotoxicidade Imunológica , Células Matadoras Naturais/imunologia , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Betacoronavirus/imunologia , Infecções por Coronavirus/sangue , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Subunidade alfa de Receptor de Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucinas/sangue , Interleucinas/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Índice de Gravidade de Doença , Adulto Jovem
5.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(5): 513-518, 2020 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-33085234

RESUMO

OBJECTIVE: To investigate the expression of glycoprotein 130 (gp130) and interleukin 12 receptor ß2 (IL-12Rß2) in two subunits of interleukin-35 receptor (IL-35R), singal transducer and activator of transcription (STAT) 1 and STAT4 in oral lichen planus (OLP) tissues, and to explore the role and significance of IL-35R in the formation and development of OLP lesions. METHODS: Totally 41 samples of OLP tissues (OLP group) and 15 samples of normal oral mucosa (control group) were collected. The expression levels of gp130, IL-12Rß2, STAT1, STAT4 mRNA in the tissues were detected by real-time fluorescent quantitative polymerase chain reaction and the distribution and expression of protein gp130 and IL-12Rß2 were detected by immunohistochemistry. The potential relationship between gp130 and IL-12Rß2 and clinical features of OLP was analyzed. RESULTS: 1) The expression levels of gp130, IL-12Rß2, STAT1 and STAT4 mRNA in the OLP group were significantly higher than those in the control group (P<0.05). 2) The positive expression rates of gp130 and IL-12Rß2 protein in the OLP group were higher than those in the control group (P<0.05). The expression of gp130 and IL-12Rß2 proteins in OLP tissues were positively correlated (r=0.984, P<0.001). 3) The expression rates of gp130 and IL-12Rß2 protein in erosive OLP tissues were significantly higher than those in non-erosive ones (P<0.05). CONCLUSIONS: The expression of IL-35R and STAT is up-regulated in OLP tissues, and the expression of IL-35R is related to the clinical classification of OLP, suggesting that IL-35R might play an important role in the formation and development of damage OLP lesions.


Assuntos
Líquen Plano Bucal , Humanos , Imuno-Histoquímica , Interleucinas , Mucosa Bucal , RNA Mensageiro
6.
Vaccine ; 38(48): 7581-7584, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33071005

RESUMO

Today, Coronavirus Disease 2019 (COVID-19) is a global public health emergency and vaccination measures to counter its diffusion are deemed necessary. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of the disease, unleashes a T-helper 2 immune response in those patients requiring intensive care. Here, we illustrate the immunological mechanism to train the immune system towards a more effective and less symptomatic T-helper 1 immune response, to be exploited against SARS-CoV-2.


Assuntos
Vacina BCG/administração & dosagem , Vacinas Bacterianas/administração & dosagem , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Imunidade Inata/efeitos dos fármacos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Propionibacteriaceae/imunologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Corynebacterium , Humanos , Esquemas de Imunização , Imunogenicidade da Vacina , Interleucinas/genética , Interleucinas/imunologia , Segurança do Paciente , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/virologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/virologia , Vacinação , Vacinas Virais/administração & dosagem , Vacinas Virais/biossíntese
7.
J Exp Med ; 217(3): e20192195, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32997932

RESUMO

The cytokine interleukin-22 (IL-22) is a critical regulator of epithelial homeostasis. It has been implicated in multiple aspects of epithelial barrier function, including regulation of epithelial cell growth and permeability, production of mucus and antimicrobial proteins (AMPs), and complement production. In this review, we focus specifically on the role of IL-22 in the intestinal epithelium. We summarize recent advances in our understanding of how IL-22 regulates homeostasis and host defense, and we discuss the IL-22 pathway as a therapeutic target in diseases of the intestine, including inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), and cancer.


Assuntos
Interleucinas/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Animais , Células Epiteliais/metabolismo , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo
8.
Rev Iberoam Micol ; 37(2): 41-46, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33041191

RESUMO

Critically ill COVID-19 patients have higher pro-inflammatory (IL-1, IL-2, IL-6, tumor necrosis alpha) and anti-inflammatory (IL-4, IL-10) cytokine levels, less CD4 interferon-gamma expression, and fewer CD4 and CD8 cells. This severe clinical situation increases the risk of serious fungal infections, such as invasive pulmonary aspergillosis, invasive candidiasis or Pneumocystis jirovecii pneumonia. However, few studies have investigated fungal coinfections in this population. We describe an update on published reports on fungal coinfections and our personal experience in three Spanish hospitals. We can conclude that despite the serious disease caused by SARS-CoV-2 in many patients, the scarcity of invasive mycoses is probably due to the few bronchoscopies and necropsies performed in these patients because of the high risk in aerosol generation. However, the presence of fungal markers in clinically relevant specimens, with the exception of bronchopulmonary colonization by Candida, should make it advisable to early implement antifungal therapy.


Assuntos
Betacoronavirus , Candidíase Invasiva/epidemiologia , Coinfecção/epidemiologia , Infecções por Coronavirus/epidemiologia , Aspergilose Pulmonar Invasiva/epidemiologia , Pneumonia por Pneumocystis/epidemiologia , Pneumonia Viral/epidemiologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por Coronavirus/sangue , Humanos , Interferon gama/sangue , Interleucinas/sangue , Pandemias , Pneumonia Viral/sangue , Espanha/epidemiologia , Fator de Necrose Tumoral alfa/sangue
9.
PLoS One ; 15(9): e0239668, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970762

RESUMO

We developed an approach for substantial attenuation of Mycobacterium tuberculosis by prolonged culturing under gradually acidifying conditions. Bacteria subjected to acidification lost the capacity to form colonies on solid media, but readily resuscitated their growth in the murine host, providing a useful model to study in vivo development of infection mimicking latent and reactivation tuberculosis (TB) in humans. Here we characterize biomarkers of lung pathology and immune responses triggered by such attenuated bacteria in genetically TB-susceptible and resistant mice. In susceptible I/St mice, CFU counts in lungs and spleens were ~1.5-log higher than in resistant B6 mice, accompanied by diffuse pneumonia and excessive lung infiltration with highly activated CD44+CD62L- T-lymphocytes resulting in death between months 7-9 post challenge. B6 mice were characterized by development of local inflammatory foci, higher production of pro-inflammatory IL-6 and IL-11 cytokines and a more balanced T-cell activation in their lungs. CFU counts remained stable in B6 mice during the whole 18-mo observation period, and all mice survived. Thus, we established a mouse model of fatal reactivation TB vs. indefinite mycobacterial possession after identical challenge and characterized the features of immune responses in the lung tissue underlining these polar phenotypes.


Assuntos
Predisposição Genética para Doença , Interleucinas/metabolismo , Pulmão/imunologia , Ativação Linfocitária , Tuberculose Pulmonar/imunologia , Tuberculose Esplênica/imunologia , Animais , Carga Bacteriana , Células Cultivadas , Feminino , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Interleucinas/genética , Selectina L/genética , Selectina L/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/patogenicidade , Baço/imunologia , Baço/microbiologia , Linfócitos T/imunologia , Tuberculose Pulmonar/genética , Tuberculose Esplênica/genética
12.
Lancet Haematol ; 7(10): e715-e723, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32976751

RESUMO

BACKGROUND: The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. METHODS: We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. FINDINGS: We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset. INTERPRETATION: Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. FUNDING: The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Interleucinas/genética , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
13.
Nat Commun ; 11(1): 4457, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901017

RESUMO

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.


Assuntos
Ácidos Graxos Voláteis/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Interleucinas/biossíntese , Animais , Butiratos/imunologia , Butiratos/metabolismo , Butiratos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Citrobacter rodentium , Colite/imunologia , Colite/microbiologia , Colite/prevenção & controle , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Interleucinas/deficiência , Interleucinas/genética , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
14.
Nat Commun ; 11(1): 4611, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929072

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Interleucinas/antagonistas & inibidores , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Québec; INESSS; 8 aout 2020.
Não convencional em Francês | BRISA/RedTESA | ID: biblio-1117465

RESUMO

CONTEXTE: Le présent document ainsi que les constats qu'il énonce ont été rédigés en réponse à une interpellation du ministère de la Santé et des Services sociaux dans le contexte de l'urgence sanitaire liée à la maladie à coronavirus (COVID-19) au Québec. L'objectif est de réaliser une recension sommaire des données publiées et de mobiliser les savoirs clés afin d'informer les décideurs publics et les professionnels de la santé et des services sociaux. Bien que les constats reposent sur un repérage exhaustif des données scientifiques publiées, la sélection et l'évaluation de la qualité méthodologique des études ne reposent pas sur une méthode systématique selon les normes habituelles à l'INESSS. Par ailleurs, les positions ne découlent pas d'un processus de consultation élaboré. Dans les circonstances d'une telle urgence de santé publique, l'INESSS reste à l'affût de toutes nouvelles données susceptibles de lui faire modifier cette réponse. POSITION DE L'INESSS: Basé sur la documentation scientifique disponible au moment de sa rédaction, et sur les consultations menées, l'INESSS estime que: TRAITEMENT COVID-19 confirmée, patients non hospitalisés: -Les biothérapies dirigées contre l'interleukine-6 (siltuximab) ou son récepteur (tocilizumab, sarilumab) ciblent un médiateur clé de la réponse immunitaire antivirale mais aussi du syndrome de libération des cytokines, une complication survenant au cours d'une phase plus tardive de l'infection. Pour ne pas nuire aux mécanismes de défense contre l'infection virale ces biothérapies ne devraient pas être envisagés chez des patients COVID-19 confirmés dont l'état clinique ne justifie pas une hospitalisation. COVID-19 confirmée, patients hospitalisés dans un état grave ou critique: -L'incertitu


Assuntos
Humanos , Interleucinas/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Avaliação em Saúde
16.
Brasília; CONITEC; ago. 2020. ilus, tab.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1122923

RESUMO

INTRODUÇÃO: A artrite psoriaca (AP) e a doenca articular inflamatoria associada a psoriase, tambem autoimune, poligenica, de etiologia indefinida, na qual as citocinas relacionadas aos linfocitos T tem um papel central como na psoriase. Estima-se que a prevalencia geral da AP esteja em torno de 0,02% a 0,25% e que 1 em cada 4 pacientes com psoriase tem artrite psoriaca: 23,8% (IC 95%: 20,1% a 27,6%). No Sistema Unico de Saude (SUS) e garantido aos pacientes o acesso as opcoes de tratamentos com medicamentos, incluindo os antiinflamatorios nao esteroidais (AINE) ibuprofeno e naproxeno; os glicocorticoides prednisona e metilprednisolona; os medicamentos modificadores do curso da doenca sinteticos (MMCD-s) sulfassalazina (SSZ), metotrexato (MTX), leflunomida e ciclosporina; os MMCD biológicos (MMCD-b) adalimumabe, etanercepte, infliximabe e golimumabe; e o inibidor de citocinas anti-IL-17 secuquinumabe. PERGUNTA: O uso de ixequizumabe e eficaz, seguro e custo-efetivo para o tratamento de pacientes adultos com AP ativa, com uma resposta insuficiente ou intolerantes ao tratamento com um MMCD biologico? TECNOLOGIA: Ixequizumabe (TaltzR). EVIDÊNCIAS CIENTÍFICAS: Uma revisao sistematica com meta-analise em rede objetivou avaliar a eficacia e seguranca comparativa dos biologicos pertencentes a classe dos inibidores da interleucina (IL-6, IL-12/23 e IL-17) em pacientes com artrite psoriaca ativa. Foi avaliado o desempenho das tecnologias quanto as respostas no instrumento ACR (ACR20, ACR50), na semana 24; qualquer evento adverso (EA); eventos adversos graves (EAG); e tolerabilidade (descontinuacao devido a EA), na semana 16 ou 24. Apos recuperar 329 estudos, a revisão incluiu 6 estudos avaliando os inibidores de interleucina secuquinumabe, ustequinumabe, clazaquizumabe e ixequizumabe, com um total de 2.411 pacientes. Na analise de risco de vies, nao foram identificados pontos criticos, exceto o fato de que todos os seis estudos relataram o uso da ultima observacao transportada para imputacao de dados ausentes (Do ingles, last observation carried forward - LOCF) e que todos os estudos incluidos receberam financiamento de um organismo comercial com fins lucrativos. Ao realizar o ranqueamento com todos os tratamentos disponiveis no SUS (nao apenas os medicamentos em discussao neste relatorio), com base nas estimativas de SUCRA, os resultados do estudo indicam que o secuquinumabe 300 mg mensalmente tem a maior efetividade na obtencao de respostas ACR20 (SUCRA = 96,42) e ACR50 (SUCRA = 91,64). O estudo tambem indica que clazaquizumabe 200mg mensalmente, ustequinumabe 45mg a cada 12 semanas e secuquinumabe 150mg mensalmente tenham a menor probabilidade de ter EA, EAG e descontinuacao devido a EA. Na relacao geral do desempenho dos tratamentos em todos os desfechos de efetividade e seguranca, o secuquinumabe se destaca como a melhor opcao de tratamento em ambas as doses de 300 mg e 150 mg e o ixequizumabe a pior opcao para o tratamento da artrite psoriaca. Apos a condução de uma atualizacao da meta-analise em rede para incluir dois novos estudos do ixequizumabe (SPIRIT-P2 e SPIRIT-H2H), nao considerados na meta-analise original, pode-se observar que o secuquinumabe ainda se mantem com maior probabilidade no ranking de melhor tratamento. Em ambos os desfechos de efetividade e seguranca, o nivel de certeza das evidencias foi considerado moderado, com reducoes de efetividade devido a limitada similaridade das populacoes estudadas com ixequizumabe, secuquinumabe, a linha de tratamento em discussão (falha aos anti-TNF) e reducoes devido a imprecisao no desfecho de EAG. AVALIAÇÃO ECONÔMICA: Para a analise economica, o demandante encaminhou um estudo de "analise de custo por resposta" ou "custo por respondedor", que foi atualizado incluindo a comparacao com o secuquinumabe. Nessa linha, ao considerar os custos e benefícios incrementais em relacao ao adalimumabe, seriam necessarios R$ 19.350,54 para cada resposta adicional no ACR50 com o secuquinumabe. O medicamento ixequizumabe nao demonstrou superioridade na obtencao do ACR50 quando comparado ao adalimumabe, mas sim no desfecho combinado do ACR50/PASI100, onde seriam necessarios R$ 71.284,24 por cada resposta adicional no ACR50/PASI100. Ressalta-se que tal analise carece do rigor metodologico das avaliacoes economicas completas e seus resultados possuem serias limitacoes de interpretacao. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O demandante encaminhou um modelo de impacto orcamentario com o objetivo de analisar o impacto da incorporacao de ixequizumabe ao longo de 5 anos no tratamento de pacientes com artrite psoriaca na perspectiva do SUS. Apos a analise critica do modelo encaminhado, considerou-se possuir um racional adequado e coerente com a perspectiva do SUS, contudo, com pontos criticos a serem revisados. Em sua proposta original, o demandante apresenta uma estimativa de economia de R$ 5,6 milhoes em cinco anos. Com a revisao e atualizacao dos dados, sobretudo ao considerar os custos do tratamento de inducao, essa economia deixa de existir e passa a ser estimado um impacto incremental de mais de R$ 58 milhoes. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas no horizonte seis potenciais tecnologias para o tratamento de pacientes com artrite psoriaca com uma resposta insuficiente ou intolerantes ao tratamento com um ou mais MMCD: apremilaste, bimequizumabe, filgotinibe, guselcumabe, risanquizumabe, upadacitinibe. CONSIDERAÇÕES: A partir das estimativas de efetividade comparativa disponiveis, por meio de meta-analises em rede, e possivel observar que o secuquinumabe, tratamento disponivel no SUS, se destaca como a melhor opcao de tratamento na indicacao dessa submissao quando comparado a outras opcoes, inclusive o ixequizumabe, que foi considerada a pior opcao para o tratamento da artrite psoriaca na relacao geral do desempenho nos desfechos de efetividade e seguranca. Alem disso, estima-se que a incorporacao do ixequizumabe possa implicar um impacto incremental de mais de R$ 58 milhoes. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A Conitec, em sua 85a reuniao ordinaria, no dia 04 de fevereiro de 2020, recomendou a nao incorporacao no SUS do ixequizumabe para artrite psoriaca ativa com resposta insuficiente ou intolerante ao tratamento com medicamentos modificadores do curso da doenca. CONSULTA PÚBLICA: Foram recebidas 134 contribuicoes tecnico-cientificas e 222 contribuicoes de experiencia ou opiniao, sendo a maioria discordante da recomendacao preliminar da Conitec. Apos analise do texto das contribuicoes, foram identificados pontos como o anseio por novas opcoes terapeuticas, dificuldade de acesso pelo alto custo unitario do medicamento, assim como foram apresentados novos dados tecnicos e ressaltadas limitacoes da analise preliminar. No entanto, nao foram fornecidas evidencias cientificas que dessem suporte a superioridade do ixequizumabe frente ao secuquinumabe ou que fornecessem melhores subsidios de comparacao do que o uso da comparacao indireta. O laboratorio fabricante ofereceu uma nova proposta de preco equivalente a reducao de 2,7% do preco proposto inicialmente e um novo modelo de impacto orcamentario indicando uma reducao de gastos de ate R$ 49.893.362,00 ao longo dos 5 anos na ocasiao de incorporacao na mesma linha e indicacao do secuquinumabe. A Conitec entendeu que nao houve argumentacao suficiente para alterar sua recomendação inicial, pela nao incorporacao do ixequizumabe, devido a incerteza de beneficios em relacao ao perfil de desempenho de efetividade e seguranca das opcoes terapeuticas ja disponiveis no SUS. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 89a reuniao ordinaria no dia 06 de agosto de 2020, deliberaram, por unanimidade, por recomendar a nao incorporacao no SUS do ixequizumabe para artrite psoriaca ativa com resposta insuficiente ou intolerante ao tratamento com medicamentos modificadores do curso da doenca. Considerou-se os mesmos argumentos para a recomendacao preliminar, o ixequizumabe nao apresenta beneficios em relacao ao perfil de desempenho de efetividade e seguranca das opcoes terapeuticas ja disponiveis no SUS. DECISÃO: Nao incorporar o ixequizumabe para tratamento de pacientes adultos com artrite psoriaca ativa com resposta insuficiente ou intolerante ao tratamento com um ou mais medicamentos modificadores do curso da doenca, no ambito do Sistema Unico de Saude - SUS, conforme Portaria no 31, publicada no Diario Oficial da Uniao no 160, secao 1, pagina 118, em 20 de agosto de 2020.


Assuntos
Humanos , Artrite Psoriásica/tratamento farmacológico , Interleucinas/uso terapêutico , Adalimumab/uso terapêutico , Infliximab/uso terapêutico , Etanercepte/uso terapêutico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
17.
Nat Med ; 26(9): 1480-1490, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32747828

RESUMO

Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8+ T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8+ T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8+ T-cell composition, including expanded effector and post-effector terminally differentiated CD8+ T cells. While UC-associated CD8+ effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8+ T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8+ T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Colite Ulcerativa/patologia , Interleucinas/metabolismo , Mucosa Intestinal/patologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Colo/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transcriptoma/genética
18.
Mol Immunol ; 126: 120-128, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32823236

RESUMO

The interleukin 12 (IL-12) family of cytokines regulates T cell functions and is key for the orchestration of immune responses. Each heterodimeric IL-12 family member is a glycoprotein. However, the impact of glycosylation on biogenesis and function of the different family members has remained incompletely defined. Here, we identify glycosylation sites within human IL-12 family subunits that become modified upon secretion. Building on these insights, we show that glycosylation is dispensable for secretion of human IL-12 family cytokines except for IL-35. Furthermore, our data show that glycosylation differentially influences IL-12 family cytokine functionality, with IL-27 being most strongly affected. Taken together, our study provides a comprehensive analysis of how glycosylation affects biogenesis and function of a key human cytokine family and provides the basis for selectively modulating their secretion via targeting glycosylation.


Assuntos
Interleucina-12/metabolismo , Interleucinas/metabolismo , Glicosilação , Células HEK293 , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-23/metabolismo , Interleucinas/genética , Interleucinas/imunologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
19.
Life Sci ; 260: 118245, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791144

RESUMO

AIMS: Bisphenol A (BPA) has been shown to induce liver fibrosis in rodents. Therefore, this study examined the protective effect of a triple combination of curcumin (Cur), N-acetyl cysteine (NAC) and propolis (Prp) extract against BPA-induced hepatic fibrosis. METHODS: 100 Wistar male rats were equally assigned into 10 groups; one group was designated as control. 10 rats were gavaged with BPA (50 mg/kg/day) for 8 wk and left un-treated (BPA group). The remaining 80 rats were divided into 8 groups, distributed in 2 models. Protective model: rats were daily co-treated with BPA and Cur (100 mg/kg, p.o) or NAC (150 mg/kg, p.o) or Prp (200 mg/kg, p.o) or their combination for 8 wk. Preventive model: rats were daily treated with Cur or NAC or Prp or their combination for 4 wk before BPA administration and then in the same manner as protective model. KEY FINDINGS: Current treatment interventions significantly alleviated BPA-induced hepatic damage and fibrosis. They also restored pro-oxidant/antioxidant balance, shifted cytokine balance towards the anti-inflammatory side, decreasing interleukin-1ß/interleukin-10 ratio. Moreover, these compounds seem to exert anti-apoptotic effects by increasing the immunoexpression of B-cell lymphoma 2 in hepatocytes and decreasing hepatic caspase-3 content. Finally, they ameliorated extracellular matrix turn over through down-regulation of matrix metalloproteinase-9 and up-regulation of tissue inhibitor of matrix metalloproteinase-2 genetic expression. SIGNIFICANCE: Current treatments guarded against BPA-induced hepatic fibrosis due to their antioxidant, anti-inflammatory and anti-apoptotic properties, decreasing extracellular matrix turnover. Interestingly, the triple therapy provided hepatoprotection superior to monotherapy. Besides, prophylactic and concurrent treatments seem to be more effective than concurrent treatments.


Assuntos
Acetilcisteína/administração & dosagem , Compostos Benzidrílicos/toxicidade , Curcumina/administração & dosagem , Cirrose Hepática/prevenção & controle , Fenóis/toxicidade , Própole/administração & dosagem , Acetilcisteína/farmacologia , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Curcumina/farmacologia , Quimioterapia Combinada , Inflamação/sangue , Interleucinas/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Masculino , Própole/farmacologia , Ratos , Ratos Wistar
20.
Proc Natl Acad Sci U S A ; 117(35): 21519-21526, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817517

RESUMO

The intestinal epithelium is a highly dynamic structure that rejuvenates in response to acute stressors and can undergo alterations in cellular composition as animals age. The microbiota, acting via secreted factors related to indole, appear to regulate the sensitivity of the epithelium to stressors and promote epithelial repair via IL-22 and type I IFN signaling. As animals age, the cellular composition of the intestinal epithelium changes, resulting in a decreased proportion of goblet cells in the colon. We show that colonization of young or geriatric mice with bacteria that secrete indoles and various derivatives or administration of the indole derivative indole-3 aldehyde increases proliferation of epithelial cells and promotes goblet cell differentiation, reversing an effect of aging. To induce goblet cell differentiation, indole acts via the xenobiotic aryl hydrocarbon receptor to increase expression of the cytokine IL-10. However, the effects of indoles on goblet cells do not depend on type I IFN or on IL-22 signaling, pathways responsible for protection against acute stressors. Thus, indoles derived from the commensal microbiota regulate intestinal homeostasis, especially during aging, via mechanisms distinct from those used during responses to acute stressors. Indoles may have utility as an intervention to limit the decline of barrier integrity and the resulting systemic inflammation that occurs with aging.


Assuntos
Células Caliciformes/efeitos dos fármacos , Células Caliciformes/microbiologia , Indóis/farmacologia , Interleucina-10/metabolismo , Microbiota/fisiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Envelhecimento/metabolismo , Animais , Bactérias/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Feminino , Células Caliciformes/citologia , Células Caliciformes/metabolismo , Interleucina-10/biossíntese , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muco/metabolismo , Transdução de Sinais
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