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1.
Allergol. immunopatol ; 50(5): 129-137, sept. 2022. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-ADZ-17

RESUMO

Background: Wenyang Pingchuan Formula (WPCF) is an empirical formula for the treatment of acute childhood asthma. However, the “time-effect” relationship of this prescription is not clear. This paper explores the relationship between Janus activated kinase signal transducer and activator of transcriptions (JAK/STAT), nuclear factor-κB (NF-κB), and microRNA (miR-19a), and also preliminarily determines the best time-effect relationship of WPCF in reducing the airway inflammation in asthmatic mice.Method: 80 BALB/c mice were randomly divided into four groups: control (CON) group, model (MDL) group, dexamethasone (DEX) group, and WPCF group. MDL group was established through intraperitoneal injection of 10% ovalbumin (OVA) and Al(OH)3 solution and the inhalation of aerosolized 5% OVA solution. Enzyme-linked immunosorbent assay (ELISA), real-time PCR and Western blot were conducted to determine the levels of interleukin (IL)-4, IL-13, interferon-γ (IFN-γ) in bronchoalveolar lavage fluid (BALF), contents of miR-19a mRNA and STAT6, phosphorylated signal transducers and activators of transcription 6 (p-STAT6), p65, phosphorylated p65 (p-p65), suppressors of cytokine signaling 1 (SOCS1), and tumor necrosis factor α-induced protein-3 (Tnfaip3) proteins after 7 and 28 days of intervention respectively.Results: Significant down-regulation of IL-4 and IL-13 expression (P<0.05) and up-regulation of IFN-γ expression (P<0.05) in BALF have been observed for WPCF group compared with the MDL group. The significant down-regulation of miR-19a mRNA and STAT6, p-STAT6, p65, p-p65 proteins (P<0.05) and up-regulation of SOCS1 and Tnfaip3 proteins (P<0.05) in BALF was also observed for WPCF group compared to the MDL group. During the experiment, the weight of the mice in DEX group significantly decreased (P<0.05) compared with the other groups.Conclusions: WPCF could restore Th1/Th2 balance (AU)


Assuntos
Humanos , Masculino , Camundongos , Asma/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Inflamação , Interferon gama/metabolismo , Interleucina-13 , NF-kappa B , Ovalbumina , RNA Mensageiro/genética
2.
Cell Rep ; 40(11): 111342, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36103837

RESUMO

Natural killer (NK) cells are lymphocytes that are involved in controlling tumors or microbial infections through the production of interferon gamma (IFN-γ). Granulocyte colony-stimulating factor (G-CSF) inhibits IFN-γ secretion by NK cells, but the mechanism underlying this effect remains unclear. Here, by comparing the multi-omics profiles of human NK cells before and after in vivo G-CSF treatment, we identify a pathway that is activated in response to G-CSF treatment, which suppresses IFN-γ secretion in NK cells. Specifically, glucocorticoid receptors (GRs) activated by G-CSF inhibit secretion of IFN-γ by promoting interactions between SOCS1 promoters and enhancers, as well as increasing the expression of SOCS1. Experiments in mice confirm that G-CSF treatment significantly downregulates IFN-γ secretion and upregulates GR and SOCS1 expression in NK cells. In addition, GR blockade by the antagonist RU486 significantly reverses the effects of G-CSF, demonstrating that GRs upregulate SOCS1 and inhibit the production of IFN-γ by NK cells.


Assuntos
Interferon gama , Células Matadoras Naturais , Animais , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Camundongos , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo
3.
Medicine (Baltimore) ; 101(35): e30073, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36107535

RESUMO

BACKGROUND: The respiratory system is the first line of defense against outside pollutants. Recently, respiratory health has been receiving increasing attention due to the increase in fine dust, which reduces respiratory function and increases incidence of chronic obstructive pulmonary disease, and in coronavirus pandemic, which can cause severe acute respiratory syndrome. METHODS: This clinical pilot trial was designed to secure evidence for a main clinical trial and to confirm the efficacy and safety of Liriope platyphylla (LP) extract for improving respiratory function. We conducted a double-blind randomized placebo-controlled trial with 22 participants from June 30, 2021, to August 25, 2021. The primary outcome was Breathlessness, Cough, and Sputum Scale score. Secondary outcomes included forced vital capacity, forced expiratory volume at 1 second (FEV1), forced expiratory volume at 1 s/forced vital capacity ratio, cough assessment test score, chronic obstructive pulmonary disease assessment test score, peripheral blood mononuclear cell counts (white blood cells, eosinophils, T cells, and B cells), high-sensitivity C-reactive protein level, erythrocyte sedimentation rate, cytokine (interleukin-1ß, interleukin-4, tumor necrosis factor-α, interleukin-6, interleukin-8, interferon-γ, and immunoglobulin E) levels, antioxidant (glutathione peroxidase and superoxide dismutase) levels, and nitric oxide level. RESULTS: A total of 22 participants were randomly assigned to 2 groups: the LP group (n = 11), who took 1000 mg of LP extract per day, and the placebo group, who took 1000 mg of dextrin per day. Participants took 1 capsule twice a day for 4 weeks. For the Breathlessness, Cough, and Sputum Scale, the interaction between group and visit was statistically significant in a blend of analyses of variance. interleukin-8, tumor necrosis factor-α, and interferon-γ levels decreased more in the LP group than in the placebo group. The sample size required for large-scale clinical trials in the future was 50. There were no side effects. CONCLUSION: LP extract can enhance respiratory function. The detailed data we obtained support conducting the future main large-scale clinical trial.


Assuntos
Interleucina-8 , Doença Pulmonar Obstrutiva Crônica , Antioxidantes/uso terapêutico , Proteína C-Reativa , Tosse/etiologia , Dextrinas/uso terapêutico , Poeira , Dispneia/complicações , Glutationa Peroxidase , Humanos , Imunoglobulina E , Interferon gama , Interleucina-1beta , Interleucina-4 , Interleucina-6/uso terapêutico , Leucócitos Mononucleares , Óxido Nítrico , Projetos Piloto , Extratos Vegetais/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/complicações , Superóxido Dismutase , Fator de Necrose Tumoral alfa/uso terapêutico
4.
J Exp Med ; 219(10)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36094518

RESUMO

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/ß (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.


Assuntos
Síndrome de Job , TYK2 Quinase , Humanos , Interferon gama/metabolismo , Interleucina-23 , Síndrome de Job/genética , TYK2 Quinase/deficiência , TYK2 Quinase/genética , TYK2 Quinase/metabolismo
5.
Medicine (Baltimore) ; 101(37): e30247, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36123839

RESUMO

BACKGROUND: A meta-analysis was performed to evaluate the effect of acupoint herbal patching as an add-on to asthma medication during Sanfu days, as the hottest days in summer, on the acute attack, immunological response, and the pulmonary function in asthmatic children. METHODS: A systematic literature search up to July 2021 was performed and 13 studies included 1166 asthmatic children at the start of the study; 587 of them were using acupoint herbal patching as an add-on to asthma medication during Sanfu days and 579 were given asthma medication only. RESULTS: Acupoint herbal patching as add-on to asthma medication had significantly lower frequency of acute attack (mean difference [MD], -1.57; 95% confidence interval [CI], -2.28 to -0.85, P < .001), lower asthma relapse (odds ratio, 0.13; 95% CI, 0.04-0.43, P < .001), and higher forced expiratory volume in 1 second (MD, 1.72; 95% CI, 0.89-2.65, P < .001), higher peak expiratory flow rate (MD, 1.15; 95% CI, 0.37-1.93, P = .004), lower immunoglobulin E after treatment (MD, -123.81; 95% CI, -185.60 to -62.02, P < .001), and higher interferon-gamma after treatment (MD, 7.17; 95% CI, 2.42-11.92, P = .003) compared to asthma medication only in asthmatic children. CONCLUSIONS: Acupoint herbal patching as an add-on to asthma medication during Sanfu days had a significantly lower frequency of acute attack, lower asthma relapse, higher forced expiratory volume in 1 second, higher peak expiratory flow rate, and higher interferon-gamma after treatment in asthmatic children compared to asthma medication only in asthmatic children.


Assuntos
Pontos de Acupuntura , Asma , Asma/tratamento farmacológico , Criança , Humanos , Imunoglobulina E , Interferon gama , Recidiva
6.
Medicine (Baltimore) ; 101(37): e30787, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36123861

RESUMO

In clinical practice, colorectal cancer (CRC) is difficult to distinguish from ulcerative colitis and colon polyps. Practical markers are useful for diagnosing and treating patients with CRC. Carcinoembryonic antigen (CEA) is a biomarker for diagnosing patients with CRC. However, the diagnostic sensitivity and specificity of CEA are not high. Interleukin (IL)-10, IL-17A, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and transforming growth factor beta (TGF-ß) are assumed to be closely related to the occurrence and development of human cancer. Some have been used as diagnostic markers in CRC. It remains unclear whether cytokines in combination with CEA could be used as biomarkers for the diagnosis of CRC. Serum levels of IL-10, IL-17, TNF-α, IFN-γ, and TGF-ß in patients with CRC, ulcerative colitis, colonic polyps, stomach cancer, and healthy controls were measured by enzyme-linked immunosorbent assay. The serum level of CEA was detected using electrochemiluminescence. The value of the cytokines combined with CEA as a biomarker panel for the diagnosis of CRC was assessed. CEA, IL-10, IL-17A, TNF-α, and TGF-ß levels were significantly increased in CRC. CEA displayed a higher specificity than the other cytokines. IL-17A, TNF-α, and TGF-ß displayed higher sensitivities than CEA, IL-10, and IFN-γ in the diagnosis of CRC. The combination of serum CEA, IL-17A, and TNF-α achieved higher diagnostic efficacy for CRC (area under the curve = 0.935). The combination of CEA, IL-17, and TNF-α has better diagnostic efficacy than CEA alone in CRC. A panel containing IL-17A, TNF-α, and CEA could be a promising molecular biomarker panel to diagnostically differentiate CRC from ulcerative colitis, colon polyps, and stomach cancer.


Assuntos
Colite Ulcerativa , Pólipos do Colo , Neoplasias Colorretais , Neoplasias Gástricas , Biomarcadores Tumorais , Antígeno Carcinoembrionário , Neoplasias Colorretais/diagnóstico , Citocinas , Humanos , Interferon gama , Interleucina-10 , Interleucina-17 , Fator de Crescimento Transformador beta , Fator de Necrose Tumoral alfa
7.
Nat Commun ; 13(1): 5422, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130936

RESUMO

T cells specific for SARS-CoV-2 are thought to protect against infection and development of COVID-19, but direct evidence for this is lacking. Here, we associated whole-blood-based measurement of SARS-CoV-2-specific interferon-γ-positive T cell responses with positive COVID-19 diagnostic (PCR and/or lateral flow) test results up to 6 months post-blood sampling. Amongst 148 participants donating venous blood samples, SARS-CoV-2-specific T cell response magnitude is significantly greater in those who remain protected versus those who become infected (P < 0.0001); relatively low magnitude T cell response results in a 43.2% risk of infection, whereas high magnitude reduces this risk to 5.4%. These findings are recapitulated in a further 299 participants testing a scalable capillary blood-based assay that could facilitate the acquisition of population-scale T cell immunity data (14.9% and 4.4%, respectively). Hence, measurement of SARS-CoV-2-specific T cells can prognosticate infection risk and should be assessed when monitoring individual and population immunity status.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Humanos , Interferon gama , Reação em Cadeia da Polimerase , Linfócitos T
8.
Allergol Immunopathol (Madr) ; 50(5): 129-137, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36086973

RESUMO

BACKGROUND: Wenyang Pingchuan Formula (WPCF) is an empirical formula for the treatment of acute childhood asthma. However, the "time-effect" relationship of this prescription is not clear. This paper explores the relationship between Janus activated kinase signal transducer and activator of transcriptions (JAK/STAT), nuclear factor-κB (NF-κB), and microRNA (miR-19a), and also preliminarily determines the best time-effect relationship of WPCF in reducing the airway inflammation in asthmatic mice. METHOD: 80 BALB/c mice were randomly divided into four groups: control (CON) group, model (MDL) group, dexamethasone (DEX) group, and WPCF group. MDL group was established through intraperitoneal injection of 10% ovalbumin (OVA) and Al(OH)3 solution and the inhalation of aerosolized 5% OVA solution. Enzyme-linked immunosorbent assay (ELISA), real-time PCR and Western blot were conducted to determine the levels of interleukin (IL)-4, IL-13, interferon-γ (IFN-γ) in bronchoalveolar lavage fluid (BALF), contents of miR-19a mRNA and STAT6, phosphorylated signal transducers and activators of transcription 6 (p-STAT6), p65, phosphorylated p65 (p-p65), suppressors of cytokine signaling 1 (SOCS1), and tumor necrosis factor α-induced protein-3 (Tnfaip3) proteins after 7 and 28 days of intervention respectively. RESULTS: Significant down-regulation of IL-4 and IL-13 expression (P<0.05) and up-regulation of IFN-γ expression (P<0.05) in BALF have been observed for WPCF group compared with the MDL group. The significant down-regulation of miR-19a mRNA and STAT6, p-STAT6, p65, p-p65 proteins (P<0.05) and up-regulation of SOCS1 and Tnfaip3 proteins (P<0.05) in BALF was also observed for WPCF group compared to the MDL group. During the experiment, the weight of the mice in DEX group significantly decreased (P<0.05) compared with the other groups. CONCLUSIONS: WPCF could restore Th1/Th2 balance. The longer the intervention time, the more effective the treatment. The down-regulation of miR-19a mRNA by activating JAK/STAT and NF-κB signal pathways may be a possible mechanism by which WPCF alleviates airway inflammation.


Assuntos
Asma , MicroRNAs , Animais , Asma/genética , Inflamação , Interferon gama/metabolismo , Interleucina-13 , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B , Ovalbumina , RNA Mensageiro/genética
9.
In Vivo ; 36(5): 2166-2172, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36099123

RESUMO

BACKGROUND/AIM: In vivo models of tuberculosis are effective tools for developing new drugs. The objective of this study was to prepare in vivo models for tuberculosis by utilizing nanocomposite particles (NCPs) containing imiquimod-loaded poly(lactic-co-glycolic acid) nanoparticles. MATERIALS AND METHODS: NCPs were prepared from dichloromethane with imiquimod and poly(lactic-co-glycolic acid) using a spray dryer. Mice were treated with NCPs in the lungs by inhalation, and then infection with Mycobacterium bovis bacille Calmette-Guerin was performed (treatment groups). The concentrations of the pro-inflammatory cytokines, tumor necrosis factor-α and interferon-γ were measured in bronchoalveolar lavage fluid using an enzyme-linked immunosorbent assay. RESULTS: When animals were treated with NCPs, the concentrations of tumor necrosis factor-α and interferon-γ in bronchoalveolar lavage fluid were significantly higher than in animals not treated with NCPs. In addition, high bacterial counts and circular granuloma were observed. CONCLUSION: NCPs prepared in this study enhanced the level of inflammation in the lungs and support the preparation of in vivo models of tuberculosis.


Assuntos
Nanocompostos , Tuberculose , Animais , Modelos Animais de Doenças , Imiquimode , Interferon gama , Ácido Láctico , Macrófagos , Camundongos , Tamanho da Partícula , Fenótipo , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Tuberculose/tratamento farmacológico , Fator de Necrose Tumoral alfa
10.
Front Immunol ; 13: 969912, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072590

RESUMO

A 56-year-old Chinese woman with previous disseminated mycobacterium avium complex infection and recurrent cervical abscesses from Burkholderia cepacia complex visited our hospital. She was diagnosed with adult-onset immunodeficiency (AOID) and tested positive for interferon-γ-neutralizing autoantibody. Ceftazidime was administered as the initial antimicrobial treatment, which was later combined with sulfamethoxazole-trimethoprim (SMZ-TMP). She developed drug rash with eosinophilia and systemic symptoms (DRESS) syndrome after SMZ-TMP administration and improved after withdrawal of the culprit antibiotic and systemic glucocorticoids treatment. Her cervical infection was eventually cured after combined therapy of long-term antibiotics and anti-IFN-γ autoantibodies (AIGA) titer-lowering treatments including glucocorticoids, rituximab, and plasmapheresis. This is the first case of DRESS syndrome in the setting of AIGA-induced AOID and is worthy of notice.


Assuntos
Síndrome de Hipersensibilidade a Medicamentos , Eosinofilia , Exantema , Síndromes de Imunodeficiência , Infecções por Mycobacterium não Tuberculosas , Adulto , Antibacterianos/uso terapêutico , Autoanticorpos , Síndrome de Hipersensibilidade a Medicamentos/complicações , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Eosinofilia/induzido quimicamente , Eosinofilia/complicações , Eosinofilia/diagnóstico , Feminino , Humanos , Interferon gama , Pessoa de Meia-Idade , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos
11.
Front Immunol ; 13: 931764, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052080

RESUMO

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved innate-like T cells capable of recognizing bacterial and fungal ligands derived from vitamin B biosynthesis. Under different stimulation conditions, MAIT cells can display different immune effector phenotypes, exerting immune regulation and anti-/protumor responses. Based on basic biological characteristics, including the enrichment of mucosal tissue, the secretion of mucosal repair protective factors (interleukin-17, etc.), and the activation of riboflavin metabolites by intestinal flora, MAIT cells may play an important role in the immune regulation effect of mucosal lesions or inflammation. At the same time, activated MAIT cells secrete granzyme B, perforin, interferon γ, and other toxic cytokines, which can mediate anti-tumor effects. In addition, since a variety of hematological malignancies express the targets of MAIT cell-specific effector molecules, MAIT cells are also a potentially attractive target for cell therapy or immunotherapy for hematological malignancies. In this review, we will provide an overview of MAIT research related to blood system diseases and discuss the possible immunomodulatory or anti-tumor roles that unique biological characteristics or effector phenotypes may play in hematological diseases.


Assuntos
Neoplasias Hematológicas , Militares , Células T Invariantes Associadas à Mucosa , Citocinas , Neoplasias Hematológicas/terapia , Humanos , Interferon gama
12.
Front Immunol ; 13: 883638, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072605

RESUMO

Background: Mucormycosis is a deadly fungal infection that mainly affects severely immunocompromised patients. We report herein the case of a previously immunocompetent adult woman who developed invasive cutaneous mucormycosis after severe burn injuries. Interferon-gamma (IFN-γ) treatment was added after failure of conventional treatment and confirmation of a sustained profound immunodepression. The diagnosis was based on a reduced expression of HLA-DR on monocytes (mHLA-DR), NK lymphopenia and a high proportion of immature neutrophils. The immune-related alterations were longitudinally monitored using panels of immune-related biomarkers. Results: Initiation of IFN-γ was associated with a rapid clinical improvement and a subsequent healing of mucormycosis infection, with no residual fungi at the surgical wound repair. The serial immunological assessment showed sharp improvements of immune parameters: a rapid recovery of mHLA-DR and of transcriptomic markers for T-cell proliferation. The patient survived and was later discharged from the ICU. Conclusion: The treatment with recombinant IFN-γ participated to the resolution of a progressively invasive mucormycosis infection, with rapid improvement in immune parameters. In the era of precision medicine in the ICU, availability of comprehensive immune monitoring tools could help guiding management of refractory infections and provide rationale for immune stimulation strategies in these high risk patients.


Assuntos
Queimaduras , Mucormicose , Adulto , Queimaduras/complicações , Terapia Combinada , Feminino , Antígenos HLA-DR , Humanos , Interferon gama/uso terapêutico , Mucormicose/diagnóstico , Mucormicose/tratamento farmacológico , Mucormicose/etiologia , Proteínas Recombinantes
13.
Medicine (Baltimore) ; 101(35): e30384, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36107562

RESUMO

Data about allergic sensitization to rhinitis among adults are limited. The objectives were to explore the prevalence of current rhinitis (CR) and associated specific allergen sensitizations in southwestern Saudi Arabia. A cross-sectional study was conducted on 969 adults in southwestern regions of Saudi Arabia, namely Aseer, Jazan, and Al Baha. From each region, 5 primary health care centers were chosen. The validated Arabic Version of the International Study of Asthma and Allergies in Childhood questionnaire was used. Total immunoglobulin E (IgE) enzyme-linked immunosorbent assay, cytokine enzyme-linked immunosorbent assay (interleukin [IL]-4, IL-10, IL-13, and interferon-γ), aeroallergen-specific IgE immunoassay (a panel of 30 common aeroallergens; 9 indoor and 21 outdoors), and eosinophilic count were assessed. A prevalence of CR of 35.8% (95% confidence interval: 32.8%-38.9%) was found. Regarding outdoor aeroallergens, Mesquite-positive IgE antibodies were higher among CR adults (odds ratio = 1.52, 95% confidence interval: 1.02-2.21) compared to those without CR. The same significant pattern was found with Chenopodium, Ragweed, Pigweed, Russian thistle, Bermuda grass, Timothy grass, and Rye. All indoor aeroallergens were not significantly associated with CR. Total IgE and eosinophil count were significantly higher among adults with CR. In conclusion, CR in southwestern regions of Saudi Arabia is common and of significant public health importance. Aeroallergens that associate with adult sensitization to CR tend to be of the outdoor variety particularly the herbaceous grass and their pollens. The magnitude of CR and its association with exposure to outdoor aeroallergens should be taken into account by health policy decision makers, clinicians, and medical practitioners when diagnosing and treating related conditions.


Assuntos
Rinite , Adulto , Alérgenos , Estudos Transversais , Humanos , Imunoglobulina E , Interferon gama , Interleucina-10 , Interleucina-13 , Arábia Saudita/epidemiologia
14.
J Immunother Cancer ; 10(9)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36109084

RESUMO

BACKGROUND: Heat shock protein 90 (HSP90) is a protein chaperone for most of the important signal transduction pathways in human epidermal growth factor receptor 2-positive (HER2+) breast cancer, including human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor and Akt. The aim of our study is to identify peptide-based vaccines and to develop an effective immunotherapeutics for the treatment of HER2+ breast cancer. METHODS: HSP90-derived major histocompatibility complex (MHC) class II epitopes were selected using in silico algorithms and validated by enzyme-linked immunospot (ELISPOT). In vivo antitumor efficacy was evaluated in MMTVneu-transgenic mice. HSP90 peptide-specific systemic T-cell responses were assessed using interferon gamma ELISPOT assay, and immune microenvironment in tumors was evaluated using multiplex immunohistochemistry and TCRß sequencing. RESULTS: First, candidate HSP90-derived MHC class II epitopes with high binding affinities across multiple human HLA class II genotypes were identified using in silico algorithms. Among the top 10 peptides, p485 and p527 were selected as promising Th1 immunity-inducing epitopes with low potential for Th2 immunity induction. The selected MHC class II HSP90 peptides induced strong antigen-specific T cell responses, which was induced by cross-priming of CD8+ T cells in vivo. The HSP90 peptide vaccines were effective in the established tumor model, and their efficacy was further enhanced when combined with stimulator of interferon genes (STING) agonist and/or anticytotoxic T lymphocyte-associated antigen-4 antibody in MMTVneu-transgenic mice. Increased tumor rejection was associated with increased systemic HSP90-specific T-cell responses, increased T-cell recruitment in tumor microenvironment, intermolecular epitope spreading, and increased rearrangement of TCRß by STING agonist. CONCLUSIONS: In conclusion, we have provided the first preclinical evidence of the action mechanism of HSP90 peptide vaccines with a distinct potential for improving breast cancer treatment.


Assuntos
Neoplasias da Mama , Receptores de Progesterona , Animais , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Epitopos , Estrogênios , Feminino , Proteínas de Choque Térmico HSP90 , Antígenos de Histocompatibilidade Classe II , Humanos , Interferon gama , Camundongos , Camundongos Transgênicos , Peptídeos , Proteínas Proto-Oncogênicas c-akt , Microambiente Tumoral , Vacinas de Subunidades
15.
Cytokine ; 159: 156005, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36084604

RESUMO

The human heterozygous 15q13.3 microdeletion is associated with neuropathological disorders, most prominently with epilepsy and intellectual disability. The 1.5 Mb deletion encompasses six genes (FAN1 [MTMR15], MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7); all but one (TRPM1) are expressed in the brain. The 15q13.3 microdeletion causes highly variable neurological symptoms, and confounding factors may contribute to a more severe phenotype. CHRNA7 and KLF13 are involved in immune system regulation and altered immune responses may contribute to neurological deficits. We used the Df[h15q13]/+ transgenic mouse model with a heterozygous deletion of the orthologous region (Het) to test the hypothesis that the microdeletion increases innate immune responses compared to wild type (WT). Male and female mice were acutely challenged with the bacteriomimetic lipopolysaccharide (LPS, 0.1 mg/kg, i.p.) or the viral mimetic polyinosinic:polycytidylic acid (Poly(I:C), 5 mg/kg). Hippocampal mRNA expression of pro-inflammatory cytokines and chemokines were determined three hours after injection using quantitative PCR analysis. In controls, expression was not affected by sex or genotype. LPS and Poly(I:C) resulted in significantly increased hippocampal expression of cytokines, chemokines, and interferon-γ (IFNγ), with more robust increases for TNF-α, IL-6, IL-1ß, CXCL1, and CCL2 by LPS, higher induction of IFNγ by Poly(I:C), and similar increases of CCL4 and CCL5 by both agents. Generally, Hets exhibited stronger responses than WT mice, and significant effects of genotype or genotype × treatment interactions were detected for CXCL1 and CCL5, and IL-6, IL-1ß, and CCL4, respectively, after LPS. Sex differences were detected for some targets. LPS but not Poly(I:C), reduced overnight burrowing independent of sex or genotype, suggesting that LPS induced sickness behavior. Thus, mice carrying the microdeletion have an increased innate immune response following a LPS challenge, but further studies will have to determine the extent and mechanisms of altered immune activation and subsequent contributions to 15q13.3 microdeletion associated deficits.


Assuntos
Deficiência Intelectual , Animais , Quimiocinas/genética , Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 15 , Citocinas/genética , Modelos Animais de Doenças , Feminino , Hipocampo , Humanos , Deficiência Intelectual/genética , Interferon gama/genética , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Poli C , RNA Mensageiro/genética , Convulsões , Canais de Cátion TRPM , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
16.
Front Immunol ; 13: 932412, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36045676

RESUMO

Immune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. Interferon gamma (IFN-γ) is known to contribute to the pathogenesis of colitis through immune modulatory mechanisms, and through direct effects on endothelial and epithelial homeostasis. Here we explore whether IFN-γ influences tumor progression by expanding the effector memory T cells (TEM) population and restricting the expression of tumor suppressors in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show that IFN-γ expression is significantly increased both in the T cells and the colonic mucosal epithelia of mice with a T cell-restricted deletion of the TGF-ß intermediate, SMAD4 (Smad4TKO). The increase of IFN-γ expression correlates with the onset of spontaneous CAC in Smad4TKO mice by 6 months of age. This phenotype is greatly ameliorated by the introduction of a germline deletion of IFN-γ in Smad4TKO mice (Smad4TKO/IFN-γKO, DKO). DKO mice had a significantly reduced incidence and progression of CAC, and a decrease in the number of mucosal CD4+ TEM cells, when compared to those of Smad4TKO mice. Similarly, the colon epithelia of DKO mice exhibited a non-oncogenic signature with a decrease in the expression of iNOS and p-STAT1, and a restoration of the tumor suppressor gene, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In vitro, treatment of human colon cancer cells with IFN-γ decreased the expression of 15-PGDH. Our data suggest that Smad4-deficient T cells promote CAC through mechanisms that include an IFN-γ-dependent suppression of the tumor suppressor 15-PGDH.


Assuntos
Neoplasias Associadas a Colite , Neoplasias do Colo , Hidroxiprostaglandina Desidrogenases/metabolismo , Interferon gama/metabolismo , Proteína Smad4/metabolismo , Animais , Colite , Neoplasias Associadas a Colite/metabolismo , Neoplasias Associadas a Colite/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Interferon gama/genética , Camundongos , Proteína Smad4/genética , Linfócitos T/metabolismo
17.
J Exp Med ; 219(11)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36048018

RESUMO

Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s and ILC3-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3 homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses, and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by the removal of adaptive immunity, interferon-γ blockade, or antibiotic treatment. Mechanistically, BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility, and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways, which in turn directly promotes the transition of precursor ILC3s to MHCII+ ILC3s. Collectively, our findings reveal that BATF is a key transcription factor for maintaining ILC3 stability and coordinating ILC3-mediated control of intestinal homeostasis.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Imunidade Inata , Linfócitos , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Cromatina/metabolismo , Homeostase , Interferon gama/metabolismo , Mucosa Intestinal , Camundongos
18.
Proc Natl Acad Sci U S A ; 119(37): e2123451119, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067301

RESUMO

Filaggrin (FLG), an essential structural protein for skin barrier function, is down-regulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin. We found that the AP1 response element within the -343/+25 of the FLG promoter was necessary for TNFα + IFNγ-induced down-regulation of FLG promoter activity. Using DNA affinity precipitation assay, we observed that AP1 subunit composition binding to the FLG promoter was altered from c-FOS:c-JUN (at the early time) to FRA1:c-JUN (at the late time) in response to TNFα + IFNγ stimulation. Knockdown of FRA1 or c-JUN abrogated TNFα + IFNγ-induced FLG suppression. Histone deacetylase (HDAC) 1 interacted with FRA1:c-JUN under TNFα + IFNγ stimulation. Knockdown of HDAC1 abrogated the inhibitory effect of TNFα + IFNγ on FLG expression. The altered expression of FLG, FRA1, c-JUN, and HDAC1 was confirmed in mouse models of 2,4-dinitrochlorobenzene-induced atopic dermatitis and imiquimod-induced psoriasis. Thus, the current study demonstrates that TNFα + IFNγ stimulation suppresses FLG expression by promoting the FRA1:c-JUN:HDAC1 complex. This study provides insight into future therapeutic strategies targeting the FRA1:c-JUN:HDAC1 complex to restore impaired FLG expression in chronic skin inflammation.


Assuntos
Proteínas Filagrinas , Histona Desacetilase 1 , Queratinócitos , Proteínas Proto-Oncogênicas c-fos , Proteínas Proto-Oncogênicas c-jun , Animais , Doença Crônica , Dermatite/genética , Dermatite/metabolismo , Regulação para Baixo , Proteínas Filagrinas/genética , Proteínas Filagrinas/metabolismo , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Interferon gama/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
19.
BMC Immunol ; 23(1): 41, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36064312

RESUMO

OBJECTIVE: CD4+CD25+Foxp3+ regulatory T (Treg) cell-mediated immunosuppression is an essential mechanism of rheumatoid arthritis (RA). However, little is known regarding the specific role of CD4+CD25-Foxp3+ Treg cells in RA. This study aimed to investigate the frequency of circulating CD4+CD25-Foxp3+ Treg cells and their role in RA. METHODS: Sixty-one untreated RA patients and 40 healthy controls (HCs) were enrolled in this study. The proportion of CD4+CD25-Foxp3+ T cells and CD4+CD25+Foxp3+ Tregs; the levels of CTLA4, GITR, Helios, and ICOS; and the production of IL-17A, IFN-γ, and IL-10 were assessed by flow cytometry. The correlation of CD4+CD25-Foxp3+ T cells and CD4+CD25+Foxp3+ Tregs with the clinical indicators was conducted by Spearman correlation analysis. RESULTS: The proportion of CD4+CD25-Foxp3+ T cells was elevated in RA and positively correlated with disease activity. CD4+CD25-Foxp3+ T cells expressed less Helios and produced more IFN-γ than conventional Tregs in RA. Additionally, the proportion of CD4+CD25-Foxp3+ T cells was positively correlated with DAS28 score, IgG titer, and anti-CCP titer. CONCLUSIONS: These data indicate that CD4+CD25-Foxp3+ T cells in RA exhibit several different functional properties from conventional Tregs and are correlated with RA disease activity.


Assuntos
Artrite Reumatoide , Fatores de Transcrição Forkhead , Humanos , Tolerância Imunológica , Interferon gama , Subunidade alfa de Receptor de Interleucina-2 , Linfócitos T Reguladores
20.
Front Immunol ; 13: 955035, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110853

RESUMO

Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γc) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γc cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.


Assuntos
Alopecia em Áreas , Inibidores de Janus Quinases , Alopecia em Áreas/tratamento farmacológico , Animais , Interferon gama/metabolismo , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Interleucina-15/metabolismo , Interleucina-2/metabolismo , Interleucina-7/metabolismo , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
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