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1.
Adv Biol Regul ; 77: 100737, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773100

RESUMO

Natural killer (NK) cells are pivotal effectors of the innate immunity protecting an individual from microbes. They are the first line of defense against invading viruses, given their substantial ability to directly target infected cells without the need for specific antigen presentation. By establishing cellular networks with a variety of cell types such as dendritic cells, NK cells can also amplify and modulate antiviral adaptive immune responses. In this review, we will examine the role of NK cells in SARS-COV2 infections causing the ongoing COVID19 pandemic, keeping in mind the controversial role of NK cells specifically in viral respiratory infections and in inflammatory-driven lung damage. We discuss lessons learnt from previous coronavirus outbreaks in humans (caused by SARS-CoV-1 and MERS-COV).


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Interações Hospedeiro-Patógeno/imunologia , Células Matadoras Naturais/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Insuficiência Respiratória/epidemiologia , Doença Aguda , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Regulação da Expressão Gênica , Imunidade Inata , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Interleucinas/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Ativação Linfocitária , Proteína 1 de Membrana Associada ao Lisossomo/genética , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
2.
Molecules ; 25(12)2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32604797

RESUMO

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Mineração de Dados/métodos , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Anti-Inflamatórios/uso terapêutico , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Bases de Dados Genéticas , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Inflamação , Interferons/genética , Interferons/imunologia , Interleucinas/genética , Interleucinas/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-32637365

RESUMO

The airway epithelial barrier is a major barrier protecting against clinically significant infections of the lung. Its integrity is often compromised due to mechanical, chemical, or infectious causes. Opportunistic bacterial pathogens are poised to cause parenchymal infection and become difficult to eradicate due to adaptive metabolic changes, biofilm formation, and the acquisition of antimicrobial resistance and fitness genes. Enhancing mucosal defenses by modulating the cytokines that regulate barrier functions, such as interleukin-22 (IL-22) and interferon-λ (IFN-λ), members of the IL-10 family of cytokines, is an attractive approach to prevent these infections that are associated with high morbidity and mortality. These cytokines both signal through the cognate receptor IL-10RB, have related protein structures and common downstream signaling suggesting shared roles in host respiratory defense. They are typically co-expressed in multiple models of infections, but with differing kinetics. IL-22 has an important role in the producing antimicrobial peptides, upregulating expression of junctional proteins in the airway epithelium and working in concert with other inflammatory cytokines such as IL-17. Conversely, IFN-λ, a potent antiviral in influenza infection with pro-inflammatory properties, appears to decrease junctional integrity allowing for bacterial and immune cell translocation. The effects of these cytokines are pleotropic, with pathogen and tissue specific consequences. Understanding how these cytokines work in the mucosal defenses of the respiratory system may suggest potential targets to prevent invasive infections of the damaged lung.


Assuntos
Interferon gama/imunologia , Subunidade beta de Receptor de Interleucina-10/imunologia , Interleucinas/imunologia , Mucosa Respiratória/imunologia , Junções Íntimas/imunologia , Infecções por Coronavirus/imunologia , Humanos , Influenza Humana/imunologia , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/imunologia , Pseudomonas aeruginosa/imunologia , Mucosa Respiratória/microbiologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia
4.
Am J Physiol Cell Physiol ; 319(3): C457-C464, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32667867

RESUMO

The inflammatory response is a complex, tightly regulated process activated by tissue wounding, foreign body invasion, and sterile inflammation. Over the decades, great progress has been made to advance our understanding of this process. One often overlooked aspect of inflammation is its sequel: resolution. We know that dysregulated resolution often results in numerous chronic degenerative diseases such as arthritis, cancer, and asthma. However, identification of components and mechanisms of resolving pathways lags behind those of proinflammatory processes, yet represents overlooked therapeutic opportunities. One approach is identification of endogenous, negative compensatory mechanisms, which are activated in response to inflammation for the purpose of resolution of that inflammatory stimuli. This review will focus on literature that describes expression and function of interleukin-19, a proposed anti-inflammatory cytokine, in numerous inflammatory diseases. The literature concerning IL-19 is complex, context-dependent, and often contradictory. The expression and function of IL-19 in the inflammatory response are in no way settled. We will attempt to clarify the role that this interesting and understudied cytokine plays in resolution of inflammation and discuss its mechanisms of action in different cell types. We will present a hypothesis that endogenous IL-19 expression in response to inflammatory stimuli is a cellular compensatory mechanism to dampen inflammation. We further present studies suggesting that while endogenously expressed IL-19 may be a response to inflammation, pharmacological levels may be necessary to effectively resolve the inflammatory cascade.


Assuntos
Citocinas/imunologia , Inflamação/tratamento farmacológico , Interleucinas/imunologia , Animais , Anti-Inflamatórios/farmacologia , Humanos , Inflamação/imunologia
5.
Proc Natl Acad Sci U S A ; 117(28): 16475-16480, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601180

RESUMO

Autism spectrum disorder (ASD) is characterized by impaired social interactions and communication. The pathogenesis of ASD is not known, but it involves activation of microglia. We had shown that the peptide neurotensin (NT) is increased in the serum of children with ASD and stimulates cultured adult human microglia to secrete the proinflammatory molecules IL-1ß and CXCL8. This process is inhibited by the cytokine IL-37. Another cytokine, IL-38, has been reported to have antiinflammatory actions. In this report, we show that pretreatment of cultured adult human microglia with recombinant IL-38 (aa3-152, 1-100 ng/mL) inhibits (P < 0.0001) NT-stimulated (10 nM) secretion of IL-1ß (at 1 ng/mL) and CXCL8 (at 100 ng/mL). In fact, IL-38 (aa3-152, 1 ng/mL) is more potent than IL-37 (100 ng/mL). Here, we report that pretreatment with IL-38 (100 ng/mL) of embryonic microglia (HMC3), in which secretion of IL-1ß was undetectable, inhibits secretion of CXCL8 (P = 0.004). Gene expression of IL-38 and its receptor IL-36R are decreased (P = 0.001 and P = 0.04, respectively) in amygdala from patients with ASD (n = 8) compared to non-ASD controls (n = 8), obtained from the University of Maryland NeuroBioBank. IL-38 is increased (P = 0.03) in the serum of children with ASD. These findings indicate an important role for IL-38 in the inhibition of activation of human microglia, thus supporting its development as a treatment approach for ASD.


Assuntos
Tonsila do Cerebelo/imunologia , Transtorno do Espectro Autista/imunologia , Interleucinas/imunologia , Microglia/imunologia , Adolescente , Transtorno do Espectro Autista/sangue , Células Cultivadas , Criança , Pré-Escolar , Humanos , Interleucina-16/sangue , Interleucina-16/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-8/imunologia , Interleucinas/sangue , Masculino , Neurotensina/sangue , Neurotensina/imunologia
6.
Biomed Pharmacother ; 128: 110316, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32505821

RESUMO

BACKGROUND: Pudilan (PDL), a four-herb prescription with the traditional function of heat-clearing and detoxifying, has been clinically used as an anti-SARS-CoV-2 infectory agent in China. PDL might also have therapeutic potentials for COVID-19 while the underlying mechanisms remain to be clarified. METHODS: We used network pharmacology analysis and selected 68 co-targeted genes/proteins as targets of both PDL and COVID-19. These co-targeted genes/proteins were predicted by SwissDock Server for their high-precision docking simulation, and analyzed by STRING for proteins to protein interaction (PPI), pathway and GO (gene ontology) enrichment. The therapeutic effect for PDL treatment on COVID-19 was validated by the TCMATCOV (TCM Anti COVID-19) platform. RESULTS: PDL might prevent the entrance of SARS-CoV-2 entry into cells by blocking the angiotensin-converting enzyme 2 (ACE2). It might inhibit the cytokine storm by affecting C-reactive protein (CRP), interferon-γ (IFN-γ), interleukin- 6 (IL-6), interleukin- 10 (IL-10), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), C-C motif chemokine ligand 5 (CCL5), transforming growth factor-ß1 (TGFß1), and other proteins. PDL might moderate the immune system to shorten the course of the disease, delay disease progression, and reduce the mortality rate. CONCLUSION: PDL might have a therapeutic effect on COVID-19 through three aspects, including the moderate immune system, anti-inflammation, and anti-virus entry into cells.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus , Síndrome da Liberação de Citocina , Medicamentos de Ervas Chinesas/farmacologia , Pandemias , Pneumonia Viral , Internalização do Vírus/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Inflamatórios/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Humanos , Fatores Imunológicos/farmacologia , Interferon gama/imunologia , Interleucinas/imunologia , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Mapas de Interação de Proteínas , Fator de Crescimento Transformador beta/imunologia
8.
Life Sci ; 252: 117663, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302624

RESUMO

AIMS: Interleukin-35 (IL-35) is a new member of the interleukin-12 family and is composed of the P35 and EB virus-inducible gene 3 subunits. The aims of this study were to examine the roles of IL-35 in the exhaustion of HBV-specific CTLs, as little as known on the subject. MAIN METHODS: The relative levels of serum HBV markers were detected using automated biochemical techniques. The HBV DNA copies were measured by RT-qPCR. The expression of inhibitory receptors and the cell cytokines on the surface of CTLs were determined by flow cytometry. The pSTAT1-pSTAT4 protein levels expression was determined by flow cytometry, confocal microscopy and Western blot. KEY FINDINGS: Our results showed that IL-35 can activate the Janus kinase 1 (JAK1)/tyrosine kinase 2 (TYK2)/signal transducer and activator of transcription 1 (STAT1)/STAT4 pathway in CTLs in vitro. Interferon-γ and tumor necrosis alpha-α expression increased in CTLs in the presence of a JAK/STAT-pathway blocker. In addition, we evaluated the expression of the exhaustion-associated molecules programmed death-1, cytotoxic T lymphocyte-associated protein-4, and lymphocyte activation gene-3 in CTLs after adding the JAK-STAT inhibitor The results showed that the expression of exhaustion-associated molecules on the CTL surface decreased after blocking the JAK-STAT pathway. IL-35 inhibited the function of HBV-specific CTLs through the JAK1/TYK2/STAT1/STAT4 pathway, and the function of CTLs was recovered after blocking the JAK/STAT pathway. SIGNIFICANCE: These data provide a new experimental basis for immunotherapy for chronic hepatitis B.


Assuntos
Antígenos E da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Interleucinas/imunologia , Linfócitos T Citotóxicos/virologia , Adulto , Citocinas/imunologia , Feminino , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/isolamento & purificação , Humanos , Janus Quinases/metabolismo , Masculino , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia
10.
J Biol Regul Homeost Agents ; 34(2): 327-331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32171193

RESUMO

Coronavirus-19 (COVI-19) involves humans as well as animals and may cause serious damage to the respiratory tract, including the lung: coronavirus disease (COVID-19). This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease. When COVI-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-6. The binding of COVI-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1ß which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1ß which is a mediator of lung inflammation, fever and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Rα receptor. IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP) kinase. This cytokine inhibits class II histocompatibility complex (MHC) molecules and inflammation in inflammatory diseases by suppressing MyD88 and subsequently IL-1ß, IL-6, TNF and CCL2. The suppression of IL-1ß by IL-37 in inflammatory state induced by coronavirus-19 can have a new therapeutic effect previously unknown. Another inhibitory cytokine is IL-38, the newest cytokine of the IL-1 family members, produced by several immune cells including B cells and macrophages. IL-38 is also a suppressor cytokine which inhibits IL-1ß and other pro-inflammatory IL-family members. IL-38 is a potential therapeutic cytokine which inhibits inflammation in viral infections including that caused by coronavirus-19, providing a new relevant strategy.


Assuntos
Infecções por Coronavirus/imunologia , Interleucina-1/imunologia , Interleucina-6/imunologia , Interleucinas/imunologia , Pneumonia Viral/imunologia , Anti-Inflamatórios , Betacoronavirus , Humanos , Pandemias
11.
Proc Natl Acad Sci U S A ; 117(11): 6047-6055, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123114

RESUMO

Interleukin (IL)-2 and IL-21 dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1 While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21-induced metabolism but caused major transcriptomic changes, including the suppression of IL-21-induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Inibidores Enzimáticos/farmacologia , Interleucinas/metabolismo , L-Lactato Desidrogenase/antagonistas & inibidores , Melanoma Experimental/terapia , Células-Tronco/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral/transplante , Humanos , Memória Imunológica , Imunoterapia Adotiva/métodos , Interleucina-2/imunologia , Interleucina-2/metabolismo , Interleucinas/imunologia , L-Lactato Desidrogenase/metabolismo , Melanoma Experimental/imunologia , Camundongos , Cultura Primária de Células , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
12.
Zool Res ; 41(2): 123-137, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32150792

RESUMO

Interleukin-34 (IL-34) is a novel cytokine that plays an important role in innate immunity and inflammatory processes by binding to the colony-stimulating factor-1 receptor (CSF-1R). However, information on the function of IL-34 in fish remains limited. In the present study, we identified an IL-34 homolog from mudskippers ( Boleophthalmus pectinirostris). In silico analysis showed that the mudskipper IL-34 (BpIL-34) was similar to other known IL-34 variants in sequence and structure and was most closely related to an orange-spotted grouper ( Epinephelus coioides) homolog. BpIL-34 transcripts were constitutively expressed in various tissues, with the highest level of expression found in the brain. Edwardsiella tarda infection significantly up-regulated the mRNA expression of BpIL-34 in the mudskipper tissues. The recombinant mature BpIL-34 peptide (rBpIL-34) was purified and used to produce anti-rBpIL-34 IgG. Western blot analysis combined with PNGase F digestion revealed that native BpIL-34 in monocytes/macrophages (MOs/MФs) was N-glycosylated. In vitro, rBpIL-34 treatment enhanced the phagocytotic and bactericidal activity of mudskipper MOs/MФs, as well as the mRNA expression of pro-inflammatory cytokines like tumor necrosis factor α ( BpTNF-α) and BpIL-1ß in these cells. Furthermore, the knockdown of mudskipper CSF-1R1 ( BpCSF-1R1), but not mudskipper BpCSF-1R2, significantly inhibited the rBpIL-34-mediated enhanced effect on MO/MФ function. In conclusion, our results indicate that mudskipper BpIL-34 modulates the functions of MOs/MФs via BpCSF-1R1.


Assuntos
Edwardsiella tarda/fisiologia , Proteínas de Peixes/genética , Peixes/genética , Interleucinas/genética , Fator Estimulador de Colônias de Macrófagos/genética , Macrófagos/imunologia , Monócitos/imunologia , Animais , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/veterinária , Doenças dos Peixes/imunologia , Proteínas de Peixes/imunologia , Peixes/imunologia , Imunidade Inata , Interleucinas/imunologia , Fator Estimulador de Colônias de Macrófagos/imunologia
13.
Immunity ; 52(3): 434-451, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187515

RESUMO

Self-maintaining resident macrophages populate all mammalian organs. In addition to their role as immune sentinels, macrophages also perform day-to-day functions essential to tissue homeostasis. The homeostatic functions of macrophages are regulated by so-called tissular "niches" that control the size of the macrophage population and imprint tissue-specific identity. Here, we review the mechanisms underlying self-maintenance of distinct macrophage populations and outline the organizing principles of the macrophage niche. We examine recent studies that uncovered mutually beneficial cell-cell circuits established between macrophages and their niche and propose a modular view of tissues that integrates the resident macrophage as an essential component of each individual module. Manipulating macrophage niche cells to control the function of resident macrophages in vivo might have therapeutic value in various disease settings.


Assuntos
Microambiente Celular/imunologia , Homeostase/imunologia , Macrófagos/imunologia , Especificidade de Órgãos/imunologia , Animais , Sobrevivência Celular/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Interleucinas/imunologia , Interleucinas/metabolismo , Fator Estimulador de Colônias de Macrófagos/imunologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo
14.
J Clin Neurosci ; 75: 176-180, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32217048

RESUMO

Data indexing the contribution of various immuno-inflammatory components in the cerebrospinal fluid (CSF) towards the pathophysiology of Guillain Barré Syndrome (GBS) are limited. Th17 pathway plays crucial role in many immune mediated disorders of the nervous system. This study was aimed at exploring the role of Th17 pathway related cytokines in the CSF of patients with GBS. Levels of multiple key cytokines of Th17 pathway in CSF of patients with GBS (N = 37) and controls (N = 37) were examined in this prospective study using Bio-plex Pro Human Th17 cytokine assays in a Multiplex Suspension Array platform. The findings were correlated with clinical features and electrophysiological subtypes. Three key cytokines of Th17 pathway (IL-6, IL-17A and IL-22) were significantly elevated in CSF of patients with GBS as compared to controls. There was a positive correlation between the levels of IL-6 and IL-17A as well as between the levels of IL-17A and IL-22 in the CSF of patients with GBS. The CSF levels of IL-6 and IL-22 were negatively correlated with the duration of symptoms of GBS. None of the studied cytokines correlated with functional disability scores at admission to hospital or with the electrophysiological subtypes. Identification of Th17 pathway signatures in CSF sheds more insights into the pathogenic role of Th17 cells in GBS. These findings complement the contemporary knowledge and tender further support towards the involvement of Th17 pathway in GBS.


Assuntos
Síndrome de Guillain-Barré/líquido cefalorraquidiano , Interleucina-17/líquido cefalorraquidiano , Interleucina-6/líquido cefalorraquidiano , Interleucinas/líquido cefalorraquidiano , Transdução de Sinais/fisiologia , Células Th17/metabolismo , Adulto , Biomarcadores/líquido cefalorraquidiano , Citocinas/líquido cefalorraquidiano , Citocinas/imunologia , Feminino , Síndrome de Guillain-Barré/imunologia , Humanos , Interleucina-17/imunologia , Interleucina-6/imunologia , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Células Th17/imunologia
15.
Microbiol Immunol ; 64(6): 458-468, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32221997

RESUMO

HIV replication can be inhibited by CXCR5+ CD8 T cells (follicular cytotoxic T cell [TFC]) which transfer into B-cell follicles where latent HIV infection persists. However, how cytokines affect TFC remain unclear. Understanding which cytokines show the ability to affect TFC could be a key strategy toward curing HIV. Similar mechanisms could be used for the growth and transfer of TFCs and follicular helper T (TFH) cells; as a result, we hypothesized that cytokines IL-6, IL-21, and transforming growth factor-ß (TGF-ß), which are necessary for the differentiation of TFH cells, could also dictate the development of TFCs. In this work, lymph node mononuclear cells and peripheral blood mononuclear cells from HIV-infected individuals were cocultured with IL-6, IL-21, and TGF-ß. We then carried out T-cell receptor (TCR) repertoire analysis to compare the differences between CXCR5- and CXCR5+ CD8 T cells. Our results showed that the percentage and function of TFC can be enhanced by stimulation with TGF-ß. Besides, TGF-ß stimulation enhanced the diversity of TCR and complementarity-determining region 3 sequences. HIV DNA showed a negative correlation with TFC. The use of TGF-ß to promote the expression of CXCR5+ CD8 T cells could become a new treatment approach for curing HIV.


Assuntos
Infecções por HIV/imunologia , Linfonodos/imunologia , Subpopulações de Linfócitos/imunologia , Receptores CXCR5/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Crescimento Transformador beta/fisiologia , Adolescente , Adulto , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , HIV-1 , Humanos , Interleucina-6/imunologia , Interleucinas/imunologia , Linfonodos/patologia , Subpopulações de Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/patologia , Linfócitos T Auxiliares-Indutores/patologia , Adulto Jovem
16.
Nature ; 579(7800): 575-580, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32050257

RESUMO

The intestinal mucosa serves both as a conduit for the uptake of food-derived nutrients and microbiome-derived metabolites, and as a barrier that prevents tissue invasion by microorganisms and tempers inflammatory responses to the myriad contents of the lumen. How the intestine coordinates physiological and immune responses to food consumption to optimize nutrient uptake while maintaining barrier functions remains unclear. Here we show in mice how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses that are controlled by type-3 innate lymphoid cells (ILC3)1-3. Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP)4. Projections of VIP-producing neurons (VIPergic neurons) in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2; also known as VPAC2). Production of interleukin (IL)-22 by ILC3, which is upregulated by the presence of commensal microorganisms such as segmented filamentous bacteria5-7, is inhibited upon engagement of VIPR2. As a consequence, levels of antimicrobial peptide derived from epithelial cells are reduced but the expression of lipid-binding proteins and transporters is increased8. During food consumption, the activation of VIPergic neurons thus enhances the growth of segmented filamentous bacteria associated with the epithelium, and increases lipid absorption. Our results reveal a feeding- and circadian-regulated dynamic neuroimmune circuit in the intestine that promotes a trade-off between innate immune protection mediated by IL-22 and the efficiency of nutrient absorption. Modulation of this pathway may therefore be effective for enhancing resistance to enteropathogens2,3,9 and for the treatment of metabolic diseases.


Assuntos
Ingestão de Alimentos/fisiologia , Imunidade Inata/imunologia , Absorção Intestinal/fisiologia , Intestinos/imunologia , Intestinos/fisiologia , Linfócitos/imunologia , Neurônios/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Ritmo Circadiano/fisiologia , Ingestão de Alimentos/imunologia , Feminino , Interleucinas/biossíntese , Interleucinas/imunologia , Absorção Intestinal/imunologia , Intestinos/citologia , Intestinos/microbiologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Período Pós-Prandial/fisiologia , Receptores CCR6/metabolismo , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Simbiose
17.
Cancer Immunol Res ; 8(3): 292-308, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32024640

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8+ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8+ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8+ T cells. Distinct from its action on CD4+ T cells, IL35 signaling in gp130+CD8+ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8+ T cells via suppression of CXCR3, CCR5, and IFNγ expression. Inhibition of STAT3 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8+ T cells was driven by B cell- but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy. Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that the presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3-CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated IL35/gp130/STAT3 signaling as an important direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.


Assuntos
Linfócitos B/imunologia , Carcinoma Ductal Pancreático/imunologia , Interleucinas/imunologia , Neoplasias Pancreáticas/imunologia , Fator de Transcrição STAT3/imunologia , Animais , Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Estudos de Casos e Controles , Proliferação de Células/fisiologia , Humanos , Imunoterapia Adotiva/métodos , Interleucinas/genética , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Receptores CCR5/genética , Receptores CCR5/imunologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Fator de Transcrição STAT3/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Adv Exp Med Biol ; 1240: 73-82, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060889

RESUMO

IL-21 is an immunomodulatory cytokine produced by natural killer (NK) cells and T cells that has pleiotropic roles in immune and nonimmune cells. IL-21 can modulate innate and specific immunity activities. It is a potent stimulator of T and natural killer cell-mediated antitumor immunity but also has pro-inflammatory functions in many tissues and is involved in oncogenesis. It is important to understand IL-21 biology in these different situations to ensure the maximal benefit of therapeutic strategies targeting this cytokine. This chapter summarizes IL-21 characteristics and signaling, its role in immune system components, and its use in cancer immunotherapies.


Assuntos
Interleucinas/imunologia , Interleucinas/metabolismo , Transdução de Sinais , Microambiente Tumoral , Animais , Carcinogênese , Humanos , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Linfócitos T/imunologia
19.
Cancer Immunol Res ; 8(3): 309-320, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953246

RESUMO

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death in the world, and curative systemic therapies are lacking. Chimeric antigen receptor (CAR)-expressing T cells induce robust antitumor responses in patients with hematologic malignancies but have limited efficacy in patients with solid tumors, including HCC. IL15 and IL21 promote T-cell expansion, survival, and function and can improve the antitumor properties of T cells. We explored whether transgenic expression of IL15 and/or IL21 enhanced glypican-3-CAR (GPC3-CAR) T cells' antitumor properties against HCC. We previously optimized the costimulation in GPC3-CARs and selected a second-generation GPC3-CAR incorporating a 4-1BB costimulatory endodomain (GBBz) for development. Here, we generated constructs encoding IL15, IL21, or both with GBBz (15.GBBz, 21.GBBz, and 21.15.GBBz, respectively) and examined the ability of transduced T cells to kill, produce effector cytokines, and expand in an antigen-dependent manner. We performed gene-expression and phenotypic analyses of GPC3-CAR T cells and CRISPR-Cas9 knockout of the TCF7 gene. Finally, we measured GPC3-CAR T-cell antitumor activity in murine xenograft models of GPC3+ tumors. The increased proliferation of 21.15.GBBz T cells was at least in part dependent on the upregulation and maintenance of TCF-1 (encoded by TCF7) and associated with a higher percentage of stem cell memory and central memory populations after manufacturing. T cells expressing 21.15.GBBz had superior in vitro and in vivo expansion and persistence, and the most robust antitumor activity in vivo These results provided preclinical evidence to support the clinical evaluation of 21.15.GPC3-CAR T cells in patients with HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Glipicanas/imunologia , Imunoterapia Adotiva/métodos , Interleucina-15/imunologia , Interleucinas/imunologia , Neoplasias Hepáticas/terapia , Animais , Apoptose/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/fisiologia , Feminino , Glipicanas/genética , Humanos , Interleucina-15/biossíntese , Interleucina-15/genética , Interleucinas/biossíntese , Interleucinas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cancer Immunol Res ; 8(3): 321-333, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31964625

RESUMO

CD8+ T cells can be polarized into several different subsets as defined by the cytokines they produce and the transcription factors that govern their differentiation. Here, we identified the polarizing conditions to induce an IL22-producing CD8+ Tc22 subset, which is dependent on IL6 and the aryl hydrocarbon receptor transcription factor. Further characterization showed that this subset was highly cytolytic and expressed a distinct cytokine profile and transcriptome relative to other subsets. In addition, polarized Tc22 were able to control tumor growth as well as, if not better than, the traditional IFNγ-producing Tc1 subset. Tc22s were also found to infiltrate the tumors of human patients with ovarian cancer, comprising up to approximately 30% of expanded CD8+ tumor-infiltrating lymphocytes (TIL). Importantly, IL22 production in these CD8+ TILs correlated with improved recurrence-free survival. Given the antitumor properties of Tc22 cells, it may be prudent to polarize T cells to the Tc22 lineage when using chimeric antigen receptor (CAR)-T or T-cell receptor (TCR) transduction-based immunotherapies.


Assuntos
Imunoterapia Adotiva/métodos , Interleucina-6/farmacologia , Interleucinas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/terapia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Polaridade Celular/imunologia , Feminino , Humanos , Interleucina-6/biossíntese , Interleucina-6/genética , Interleucina-6/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Hidrocarboneto Arílico/imunologia , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma , Células Tumorais Cultivadas
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