RESUMO
OBJECTIVES: Alveolar echinococcosis (AE) represents one of the deadliest helminthic infections, characterized by an insidious onset and high lethality. METHODS: This study utilized the Gene Expression Omnibus (GEO) database, applied Weighted Correlation Network Analysis (WGCNA) and Differential Expression Analysis (DEA), and employed the Matthews Correlation Coefficient (MCC) to identify CCL17 and CCL19 as key genes in AE. Immunohistochemistry and immunofluorescence co-localization techniques were used to examine the expression of CCL17 and CCL19 in liver tissue lesions of AE patients. Additionally, a mouse model of multilocular echinococcus larvae infection was developed to study the temporal expression patterns of these genes, along with liver fibrosis and inflammatory responses. RESULTS: The in vitro model simulating echinococcal larva infection mirrored the hepatic microenvironment post-infection with multilocular echinococcal tapeworms. Quantitative RT-PCR analysis showed that liver fibrosis occurred in AE patients, with proximal activation and increased expression of CCL17 and CCL19 over time post-infection. Notably, expression peaked during the late stages of infection. Similarly, F4/80, a macrophage marker, exhibited corresponding trends in expression. Upon stimulation of normal hepatocytes by vesicular larvae in cellular experiments, there was a significant increase in CCL17 and CCL19 expression at 12 h post-infection, mirroring the upregulation observed with F4/80. CONCLUSION: CCL17 and CCL19 facilitate macrophage aggregation via the chemokine pathway and their increased expression correlates with the progression of infection, suggesting their potential as biomarkers for AE progression.
Assuntos
Biomarcadores , Quimiocina CCL17 , Quimiocina CCL19 , Progressão da Doença , Animais , Humanos , Camundongos , Biomarcadores/metabolismo , Quimiocina CCL19/metabolismo , Quimiocina CCL17/metabolismo , Quimiocina CCL17/genética , Equinococose/metabolismo , Cirrose Hepática/parasitologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Modelos Animais de Doenças , Fígado/parasitologia , Fígado/metabolismo , Fígado/patologia , Equinococose Hepática/metabolismo , Equinococose Hepática/parasitologia , Feminino , Masculino , Hepatócitos/metabolismo , Hepatócitos/parasitologiaRESUMO
BACKGROUND: Atopic dermatitis has a marked economic impact and affects the quality of life. A cosmetic compound with an innovative strategy is proposed here as a small chemical neutraligand, GPN279 (previously identified as a theophylline derivative), that binds and potently neutralizes the TARC/CCL17 chemokine, activating the Th2 cell-expressed CCR4 receptor. OBJECTIVE: Our objective was to evaluate the safety and activity of topically applied GPN279 in mild-to-moderate atopic dermatitis patients in a randomized, double-blind, placebo-controlled, parallel group trial. Such cosmetic active ingredient targeting dry skin with an atopic tendency would open a parallel strategy to the pharmaceutical approach, in particular for mild to moderate subjects, as an alternative to reduce the evolution towards severe forms of atopy. METHODS: This 4-week trial included adults with mild-to-moderate atopic dermatitis, according to the SCORAD index. Patients were randomized into two groups treated by topical applications of either an emulsion containing 0.44% GPN279 in placebo on skin lesions or the placebo (4.56% glycerin). Clinical activity was evaluated with the SCORAD as the primary objective. As secondary objectives, POEM, erythema, skin moisturization, its barrier function (TEWL) and safety were evaluated. RESULTS: Twenty-one patients in each group completed the study. SCORAD was significantly improved in the GPN279 group vs. placebo. GPN279 also significantly improved POEM, induced a rapid and significant decrease of erythema, and improved skin moisture. GPN279 and placebo were well tolerated throughout the study. CONCLUSION: A cosmetic cream comprising the CCL17 neutraligand GPN279 improved the skin barrier and physiology criteria in patients with mild-to-moderate atopic dermatitis.
GÉNÉRALITÉS: La dermatite atopique a un impact économique marqué et affecte la qualité de vie. Un composé cosmétique dote d'une stratégie innovante est proposé ici sous la forme d'un petit neutraligand chimique, le GPN279 (précédemment identifié comme un dérivé de la théophylline), qui se lie et neutralise puissamment la chimiokine TARC/CCL17, activant le récepteur CCR4 exprimé par les cellules Th2. OBJECTIF: Notre objectif était d'évaluer l'innocuité et l'activité du GPN279 appliqué localement chez des patients atteints de dermatite atopique légère à modérée dans un essai randomisé, en double aveugle contre placebo et en groupes parallèles. Un tel actif cosmétique ciblant les peaux sèches à tendance atopique ouvrirait une stratégie parallèle à l'approche pharmaceutique, notamment pour les sujets atteints de forme légère à modérée, comme alternative visant à réduire l'évolution vers des formes sévères d'atopie. MÉTHODES: Cet essai de 4 semaines incluait des adultes atteints de dermatite atopique légère à modérée, selon l'indice SCORAD. Les patients ont été randomisés en deux groupes traités par application topique sur les lésions cutanées soit d'une émulsion contenant 0,44% de GPN279 dans un placebo, soit du placebo seul (4,56% de glycérine). L'activité clinique a été évaluée selon l'indice SCORAD comme objectif principal. Les objectifs secondaires évaluaient le POEM, l'érythème, l'hydratation de la peau, sa fonction barrière (TEWL) et la sécurité. RÉSULTATS: Vingt et un patients de chaque groupe ont terminé l'étude. L'indice SCORAD a été significativement amélioré dans le groupe GPN279 par rapport au placebo. Le GPN279 a également amélioré de manière significative le POEM, a induit une diminution rapide et significative de l'érythème et amélioré l'hydratation de la peau. Le GPN279 et le placebo ont été bien tolérés tout au long de l'étude. CONCLUSION: Une crème cosmétique contenant le neutraligand CCL17 GPN279 améliore la barrière cutanée et les critères physiologiques chez les patients atteints de dermatite atopique légère à modérée.
Assuntos
Administração Tópica , Quimiocina CCL17 , Dermatite Atópica , Humanos , Dermatite Atópica/tratamento farmacológico , Método Duplo-Cego , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Cosméticos/administração & dosagem , Placebos/administração & dosagemRESUMO
BACKGROUND: Atopic dermatitis (AD) is a common and recurrent inflammatory disease with strong genetic susceptibility. The abnormal production of chemokines plays an important role in the occurrence and development of AD. METHODS: A comprehensive online literature search was performed in databases of China National Knowledge Infrastructure, Wanfang, VIP China Science and Technology Journal Database, China Biomedical Literature Database, PubMed, Embase and Cochrane Library to retrieve relevant articles published from January 2000 to October 2022. The odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate this relationship. RESULTS: A total of 7 studies were finally screened out, including 1316 AD patients and 1099 controls. There were 3 studies for CC chemokine ligand 5 (CCL5) polymorphisms, 2 for CCL11 polymorphisms, and 2 for CCL17 polymorphisms, respectively. The meta-analysis revealed a significant association between the CCL5â -â 403G/A polymorphism and AD under the allelic model (A vs G: ORâ =â 1.25, 95% CIâ =â 1.02-1.52, Pâ =â .03), heterozygous model (AG vs GG: ORâ =â 1.40, 95% CIâ =â 1.08-1.80, Pâ =â .01) and dominant model (AAâ +â AG vs GG: ORâ =â 1.38, 95% CIâ =â 1.08-1.76, Pâ =â .01) in a fixed-effect model. The allelic model (G vs C: ORâ =â 1.46, 95% CIâ =â 1.07-1.98, Pâ <â .01) and dominant model (GGâ +â GC vs CC: ORâ =â 1.74, 95% CIâ =â 1.23-2.47, Pâ <â .001) of the CCL5â -â 28C/G polymorphism were also associated with an increased risk of AD. However, this significant association was not found in other alleles and genotypes (Pâ >â .05). CONCLUSION: Our results show that the A allele, AG and AAâ +â AG genotypes of the CCL5â -â 403G/A polymorphism, the G allele and GGâ +â GC genotype of the CCL5â -â 28C/G polymorphism are risk factors for AD. Future studies with large population are still needed to further explore those correlations.
Assuntos
Quimiocina CCL11 , Quimiocina CCL17 , Quimiocina CCL5 , Dermatite Atópica , Humanos , Quimiocina CCL11/genética , Quimiocina CCL17/genética , Quimiocina CCL5/genética , Dermatite Atópica/genética , Predisposição Genética para Doença , Genótipo , Ligantes , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
To date, most studies to identify biomarkers associated with response to the anti-interleukin 5 agent, mepolizumab, and to the anti-immunoglobulin E agent, omalizumab have focused on clinically available biomarkers, such as the peripheral blood eosinophil counts (BEC) and total immunoglobulin E (IgE). However, these biomarkers often have low predictive accuracy, with many patients with eosinophilic or allergic asthma failing to demonstrate clinical response to mepolizumab or omalizumab respectively. In this study, we evaluated the association of baseline pre-biologic plasma levels of 26 cytokines and chemokines, including T-helper 1 (Th1)-, Th2-, Th17-related cytokines, and their ratios with subsequent clinical response to mepolizumab or omalizumab. We defined clinical response as a reduction in the baseline annual exacerbation rate by half or more over the one-year period following initiation of the biologic. Baseline levels of plasma IL-13 were differentially elevated in responders versus non-responders to mepolizumab and plasma CXCL10 levels were differentially elevated in responders to omalizumab. The ratio of IL-13/TNF-α had the best sensitivity and specificity in predicting response to mepolizumab and CXCL10/CCL17 to omalizumab, and these performed better as predictive biomarkers of response than BEC and IgE. Cytokines and chemokines associated with airway eosinophilia, allergic inflammation, or Th2 inflammation, such as IL-13 and CXCL10, may be better predictors of clinical response to mepolizumab and omalizumab, than IL-5 or IgE, the targets of mepolizumab and omalizumab.
Assuntos
Anticorpos Monoclonais Humanizados , Asma , Quimiocina CCL17 , Quimiocina CXCL10 , Eosinófilos , Imunoglobulina E , Interleucina-13 , Omalizumab , Humanos , Asma/tratamento farmacológico , Asma/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Omalizumab/uso terapêutico , Imunoglobulina E/sangue , Feminino , Masculino , Quimiocina CCL17/sangue , Adulto , Pessoa de Meia-Idade , Quimiocina CXCL10/sangue , Interleucina-13/sangue , Fator de Necrose Tumoral alfa/sangue , Biomarcadores/sangue , Antiasmáticos/uso terapêutico , Contagem de Leucócitos , Resultado do TratamentoRESUMO
Bullous pemphigoid (BP) is a type 2 inflammation- and immunity-driven skin disease, yet a comprehensive understanding of the immune landscape, particularly immune-stromal crosstalk in BP, remains elusive. Herein, using single-cell RNA sequencing (scRNA-seq) and in vitro functional analyzes, we pinpoint Th2 cells, dendritic cells (DCs), and fibroblasts as crucial cell populations. The IL13-IL13RA1 ligand-receptor pair is identified as the most significant mediator of immune-stromal crosstalk in BP. Notably, fibroblasts and DCs expressing IL13RA1 respond to IL13-secreting Th2 cells, thereby amplifying Th2 cell-mediated cascade responses, which occurs through the specific upregulation of PLA2G2A in fibroblasts and CCL17 in myeloid cells, creating a positive feedback loop integral to immune-stromal crosstalk. Furthermore, PLA2G2A and CCL17 contribute to an increased titer of pathogenic anti-BP180-NC16A autoantibodies in BP patients. Our work provides a comprehensive insight into BP pathogenesis and shows a mechanism governing immune-stromal interactions, providing potential avenues for future therapeutic research.
Assuntos
Quimiocina CCL17 , Células Dendríticas , Fibroblastos , Penfigoide Bolhoso , Análise de Célula Única , Células Th2 , Humanos , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/genética , Análise de Célula Única/métodos , Fibroblastos/metabolismo , Fibroblastos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Quimiocina CCL17/genética , Quimiocina CCL17/metabolismo , Células Th2/imunologia , Autoanticorpos/imunologia , Transcriptoma , Interleucina-13/metabolismo , Interleucina-13/genética , Interleucina-13/imunologia , Colágenos não Fibrilares/imunologia , Colágenos não Fibrilares/genética , Colágenos não Fibrilares/metabolismo , Inflamação/imunologia , Inflamação/genética , Inflamação/metabolismo , Perfilação da Expressão Gênica/métodos , Masculino , Feminino , Autoantígenos/imunologia , Autoantígenos/metabolismo , Autoantígenos/genética , Colágeno Tipo XVII , Células Mieloides/metabolismo , Células Mieloides/imunologia , Células Estromais/metabolismo , Células Estromais/imunologiaRESUMO
BACKGROUND AND PURPOSE: Lung macrophages (LMs) are critically involved in respiratory diseases. The primary objective of the present study was to determine whether or not an adenosine analog (NECA) and prostaglandin E2 (PGE2) affected the interleukin (IL)-4- and IL-13-induced release of M2a chemokines (CCL13, CCL17, CCL18, and CCL22) by human LMs. EXPERIMENTAL APPROACH: Primary macrophages isolated from resected human lungs were incubated with NECA, PGE2, roflumilast, or vehicle and stimulated with IL-4 or IL-13 for 24 h. The levels of chemokines and PGE2 in the culture supernatants were measured using ELISAs and enzyme immunoassays. KEY RESULTS: Exposure to IL-4 (10 ng/mL) and IL-13 (50 ng/mL) was associated with greater M2a chemokine production but not PGE2 production. PGE2 (10 ng/mL) and NECA (10-6 M) induced the production of M2a chemokines to a lesser extent but significantly enhanced the IL-4/IL-13-induced production of these chemokines. At either a clinically relevant concentration (10-9 M) or at a concentration (10-7 M) that fully inhibited phosphodiesterase 4 (PDE4) activity, roflumilast did not increase the production of M2a chemokines and did not modulate their IL-13-induced production, regardless of the presence or absence of PGE2. CONCLUSIONS: NECA and PGE2 enhanced the IL-4/IL-13-induced production of M2a chemokines. The inhibition of PDE4 by roflumilast did not alter the production of these chemokines. These results contrast totally with the previously reported inhibitory effects of NECA, PGE2, and PDE4 inhibitors on the lipopolysaccharide-induced release of tumor necrosis factor alpha and M1 chemokines in human LMs.
Assuntos
Adenosina , Aminopiridinas , Benzamidas , Dinoprostona , Humanos , Dinoprostona/farmacologia , Adenosina/farmacologia , Interleucina-4/farmacologia , Interleucina-13/farmacologia , Adenosina-5'-(N-etilcarboxamida)/farmacologia , Quimiocinas , Macrófagos , Fator de Necrose Tumoral alfa/farmacologia , Quimiocina CCL17 , Pulmão , Células Cultivadas , CiclopropanosRESUMO
Food protein-induced enterocolitis syndrome (FPIES) caused by fish and others is prevalent in the Mediterranean regions but is less frequently reported in Japan. This case report describes a 3-year-old Japanese girl who developed FPIES triggered by multiple seafoods, including swordfish, cod, and squid. The diagnosis was confirmed through oral food challenge tests (OFC), which led to repeated vomiting and an increase in thymus and activation-regulated chemokine (TARC) levels. This case highlights the importance of considering fish-induced FPIES in the differential diagnosis of recurrent vomiting in children and suggests the potential utility of TARC levels in diagnosing and monitoring FPIES.
Assuntos
Enterocolite , Hipersensibilidade Alimentar , Alimentos Marinhos , Humanos , Enterocolite/etiologia , Enterocolite/diagnóstico , Feminino , Pré-Escolar , Alimentos Marinhos/efeitos adversos , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/etiologia , Japão , Animais , Síndrome , Quimiocina CCL17/sangue , Decapodiformes , População do Leste AsiáticoRESUMO
Dengue fever poses a significant global health threat, with symptoms including dengue hemorrhagic fever and dengue shock syndrome. Each year, India experiences fatal dengue outbreaks with severe manifestations. The primary cause of severe inflammatory responses in dengue is a cytokine storm. Individuals with a secondary dengue infection of a different serotype face an increased risk of complications due to antibody-dependent enhancement. Therefore, it is crucial to identify potential risk factors and biomarkers for effective disease management. In the current study, we assessed the prevalence of dengue infection in and around Aligarh, India, and explored the role of cytokines, including CXCL5, CXCL9, and CCL17, in primary and secondary dengue infections, correlating them with various clinical indices. Among 1,500 suspected cases, 367 tested positive for dengue using Real-Time PCR and ELISA. In secondary dengue infections, the serum levels of CXCL5, CXCL9, and CCL17 were significantly higher than in primary infections (P < 0.05). Dengue virus (DENV)-2 showed the highest concentrations of CXCL5 and CCL17, whereas DENV-1 showed the highest concentrations of CXCL9. Early detection of these cytokines could serve as potential biomarkers for diagnosing severe dengue, and downregulation of these cytokines may prove beneficial for the treatment of severe dengue infections.
Assuntos
Biomarcadores , Quimiocina CCL17 , Quimiocina CXCL5 , Quimiocina CXCL9 , Dengue , Humanos , Biomarcadores/sangue , Dengue/diagnóstico , Dengue/imunologia , Dengue/sangue , Masculino , Adulto , Feminino , Índia/epidemiologia , Quimiocina CXCL5/sangue , Quimiocina CCL17/sangue , Quimiocina CXCL9/sangue , Adulto Jovem , Adolescente , Pessoa de Meia-Idade , Vírus da Dengue/imunologia , Ensaio de Imunoadsorção Enzimática , Criança , Reação em Cadeia da Polimerase em Tempo RealRESUMO
PURPOSE: Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor's immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC. METHODS: 873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software. RESULTS: The investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE. CONCLUSION: This comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification.
Assuntos
5'-Nucleotidase , Biomarcadores Tumorais , Carcinoma Hepatocelular , Quimiocina CCL17 , Proteínas Ligadas por GPI , Neoplasias Hepáticas , Receptores CCR4 , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/imunologia , Quimiocina CCL17/metabolismo , Feminino , Masculino , Prognóstico , Receptores CCR4/metabolismo , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , 5'-Nucleotidase/metabolismo , Estudos Retrospectivos , Microambiente Tumoral/imunologia , Proteínas Ligadas por GPI/metabolismo , Idoso , AdultoRESUMO
Cutaneous drug reactions (CDRs) are common drug-induced allergic reactions that cause severe consequences in HIV/AIDS patients. The CCL17/CCR4 axis is involved in the immune mechanism of allergic diseases, but its role in the CDRs has not been determined. Here, we aimed to determine the role of the CCL17/CCR4 axis and the underlying mechanism involved in CDRs. In this study, the serum cytokine levels in patients with CDR and healthy controls were measured. The CCL17-triggered allergic profile was screened via a PCR array. Apoptosis of keratinocytes cocultured with CCL17-stimulated Th2 cells was analyzed by flow cytometry. An NVP-induced rat CDR model was established, and dynamic inflammatory factor levels and Th2 cells in the peripheral blood of the rats were measured. Rat skin lesions and signaling pathways in Th2 cells were also analyzed. We showed that the serum CCL17 level was significantly upregulated in CDR patients (P = 0.0077), and the Th2 cell subgroup was also significantly elevated in the CDR rats. The CCL17/CCR4 axis induces Th2 cells to release IL-4 and IL-13 via the ERK/STAT3 pathway. The CCR4 antagonist compound 47 can alleviate rash symptoms resulting from NVP-induced drug eruption, Th2 cell subgroup, IL-4, and IL-13 and inhibit keratinocyte apoptosis. Taken together, these findings indicate that the CCL17/CCR4 axis mediates CDR via the ERK/STAT3 pathway in Th2 cells and type 2 cytokine-induced keratinocyte apoptosis.
Assuntos
Interleucina-13 , Células Th2 , Humanos , Ratos , Animais , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Citocinas/metabolismo , Transdução de Sinais , Receptores CCR4/metabolismo , Quimiocina CCL17/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
The objective of this study was to investigate the immune mechanisms involved in preterm labor (PTL), preterm prelabor rupture of the membranes (PPROM), and normal pregnancies. The second objective was to explore immune profiles in PTL for association with early ( < 34 gestational weeks (gw)) or instant ( < 48â¯h) delivery. This prospective observational multi-center study included women with singleton pregnancies with PTL (n = 80) or PPROM (n = 40) before 34 gw, women with normal pregnancies scheduled for antenatal visits (n = 44), and women with normal pregnancies in active labor at term (n = 40). Plasma samples obtained at admission were analyzed for cytokine and chemokine quantification using a multiplex bead assay in order to compare the immune profiles between PTL, PPROM, and normal pregnancies. In PTL, CXCL1 and CCL17 were significantly higher compared to gestational age-matched women at antenatal visits, whereas for PPROM, CXCL1 and IL-6 were increased. Women in term labor had a more pronounced inflammatory pattern with higher levels of CXCL1, CXCL8, and IL-6 compared with PTL (p = 0.007, 0.003, and 0.013, respectively), as well as higher levels of CCL17, CXCL1 and IL-6 (all p < 0.001) compared with the women at antenatal visits. In PTL, CXCL8 was higher in women with delivery before 34 gw, whereas CXCL8, GM-CSF, and IL-6 were significantly higher in women with delivery within 48â¯h. To conclude, PTL and PPROM were associated with a complex pattern of inflammation, both involving Th17 (CXCL1) responses. Although further studies are needed, CXCL8, GM-CSF, and IL-6 may be potential candidates for predicting preterm birth in PTL.
Assuntos
Ruptura Prematura de Membranas Fetais , Trabalho de Parto Prematuro , Humanos , Feminino , Gravidez , Ruptura Prematura de Membranas Fetais/sangue , Ruptura Prematura de Membranas Fetais/imunologia , Adulto , Trabalho de Parto Prematuro/imunologia , Trabalho de Parto Prematuro/sangue , Trabalho de Parto Prematuro/diagnóstico , Estudos Prospectivos , Citocinas/sangue , Quimiocinas/sangue , Interleucina-6/sangue , Idade Gestacional , Quimiocina CXCL1/sangue , Quimiocina CXCL1/metabolismo , Quimiocina CCL17RESUMO
INTRODUCTION: Stapokibart, a novel humanized anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits the signaling of IL-4 and IL-13, which are key drivers of type 2 inflammation in atopic dermatitis (AD). This study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of stapokibart in a randomized, double-blind, placebo-controlled single ascending dose (SAD) study and a multiple ascending dose (MAD) study. METHODS: The SAD study enrolled 33 healthy male adults aged 18-65 years at a single center. The MAD study enrolled 39 patients with moderate-to-severe AD aged 18-70 years at seven centers. Enrolled subjects were randomized to subcutaneous (SC) doses of stapokibart (75-600 mg) or placebo. Serum thymus and activation-regulated chemokine (TARC) and total immunoglobulin E (IgE) were measured as PD biomarkers for stapokibart. RESULTS: Similar PK characteristics were observed in healthy volunteers and subjects with AD after the initial administration. Stapokibart exhibited non-linear pharmacokinetics in both types of subjects. Following single doses, the mean maximum serum concentration (Cmax) ranged from 5.3 to 63.0 µg/mL, median Tmax ranged from 3.0 to 7.0 days, mean terminal half-life (t1/2z) ranged from 2.39 to 7.43 days, and mean apparent volume (Vz/F) ranged from 3.64 to 6.73 L in healthy subjects. The mean AUC accumulation ratio was 2.29 in subjects with AD after three doses of stapokibart 300 mg administered every 2 weeks. The median serum total IgE and TARC levels on day 43 decreased from baseline by 14.9-25.2% and 48.6-77.0%, respectively, among subjects with AD receiving three doses of stapokibart. No subjects developed grade ≥ 3 adverse events (AEs) or serious AEs or discontinued the study because of AEs. The incidence of AEs was similar between stapokibart and placebo groups. CONCLUSION: Stapokibart showed favorable pharmacokinetics, pharmacodynamics, safety, and tolerability in the SAD and MAD studies. Based on these results, phase II and phase III trials of stapokibart have been performed in subjects with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT06161090 (29 November, 2023), NCT04893941 (15 May, 2021).
Assuntos
Anticorpos Monoclonais Humanizados , Dermatite Atópica , Voluntários Saudáveis , Humanos , Dermatite Atópica/tratamento farmacológico , Adulto , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Adulto Jovem , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Idoso , Quimiocina CCL17/sangue , Adolescente , Relação Dose-Resposta a Droga , Imunoglobulina E/sangue , Injeções Subcutâneas , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidoresRESUMO
INTRODUCTION: The severity and clinical outcome of COVID-19 depend on virus-specific factors and the host's inflammatory response. Identifying biomarkers of severe COVID-19 is a crucial condition and predicts disease severity. METHODOLOGY: This study enrolled a total of 167 patients with COVID-19. These patients were categorized into three groups based on the severity of the disease: moderate course - 78 individuals, severe course - 52 individuals, and extremely severe course - 37 individuals. We analyzed chemokines (IP-10, CXCL9, CCL17) and cytokine IL28B levels using the enzyme immunoassay (EIA) method. RESULTS: CXCL9 levels were increased in severe and extremely severe cases compared to moderate ones. The CCL17 chemokine demonstrated significant elevation in severe cases. However, there was no significant difference in the level of IP-10, and IL28B in the compared groups. CONCLUSIONS: Our findings suggest that CXCL9 and CCL17 chemokines could be used as biomarkers to assess the clinical status of patients with COVID-19 and can relate to disease severity. These biomarkers could aid in identifying patients at high risk for severe disease and help guide clinical decision-making for the effective management of COVID-19.
Assuntos
Biomarcadores , COVID-19 , Quimiocina CXCL9 , Índice de Gravidade de Doença , Humanos , Quimiocina CXCL9/sangue , Biomarcadores/sangue , COVID-19/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , SARS-CoV-2 , Quimiocina CCL17/sangueRESUMO
Background Several markers that influence the clinical course of atopic dermatitis (AD) have been investigated so far. Thymus and activation regulated chemokine (TARC) a Th2-related cytokine increase in various atopic diseases. It has been shown that vitamin D affects Treg cells and immune responses. Zinc as an essential trace element for cellcell interactions, cellular differentiation, and proliferation. However, the effect of these markers on infantile AD and disease severity are mostly unknown. Objective The aim of this study was to investigate the relationship between TARC, vitamin D, zinc levels, and the disease severity in infants with AD. Method AD patients (n = 160) with age and sex that matched healthy controls (n = 79) were included in the study. The diagnosis of AD was made based on the HanifinRajka criteria. The objective SCORAD index was used for the assessment of disease severity. Results A total of 160 patients (male 71.9%) with AD were included in the study. The median age of onset of symptoms was 2 (1.03.5) months. The lesions initially started on face 76.9%, neck 6.9%, extremities 7.5%, and body 8.8%. Nearly 40% of the patients were found to be atopic. Food allergy was found in 39.4%. The median of objective SCORAD index was 27.5 (17.540) in the study group. The TARC levels of AD patients were higher than control group [1803 pg/ml (1006 3123) vs 709 pg/ml (5041147), p < 0.001] There was a significant correlation between objective SCORAD scores and TARC values in subjects with AD (r = 0.363, p < 0.001). As the severity of AD increased, vitamin D levels decreased (p for trend 0.015) and TARC values increased (p for trend < 0.001). Serum zinc levels did not change with the severity of the disease. The presence of atopy did not have an influence on serum TARC, zinc, and vitamin D levels. Conclusion In infants with AD, disease severity is positively related with TARC levels; and inversely proportional to vitamin D levels (AU)
Assuntos
Humanos , Masculino , Feminino , Lactente , Quimiocina CCL17/sangue , Dermatite Atópica/sangue , Vitamina D/sangue , Zinco/sangue , Índice de Gravidade de Doença , Estudos de Casos e Controles , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Idade de Início , FenótipoRESUMO
ABSTRACT BACKGROUND: During the Helicobacter pylori (HP) infection, the infiltration of the leukocytes into stomach mucosa is directed by locally produced chemokines that play a decisive role in infection outcome. The CagA is the most potent virulence factor of HP, so that the infection with CagA + strains is associated with more severe complications than infection with CagA - HP. OBJECTIVE: The aim was to determine the expression of chemokines CXCL10, CCL17, CCL20 and CCL22, and their receptors by CagA + HP- and CagA - HP-derived crude extract (HP-CE)-stimulated peripheral blood mononuclear cells (PBMCs) from peptic ulcer (PU) patients. METHODS: The serum and the PBMCs were collected from 20 HP-infected PU patients, 20 HP-infected asymptomatic subjects (HIA) and 20 non-infected healthy subjects (NHS). The PBMCs were cultured in absence of stimulator or with 10 µg CagA + HP crude extract (CagA + CE), 10 µg CagA - HP crude extract (CagA - CE). Chemokines and receptors were measured by ELISA and real time-PCR respectively. RESULTS: In PU patients, the production of chemokines CXCL10, CCL17, CCL20 and CCL22, and the expression of chemokine receptors CXCR3, CCR4 and CCR6 by CagA + CE-induced PBMCs were significantly higher than non-stimulated and CagA - CE stimulated cultures. The CXCL10 production by CagA + CE stimulated PBMCs from HIA subjects was significantly higher than the equal cultures from PU and NHS groups. The CCL17 and the CCL20 production by non-stimulated, CagA + CE stimulated, and CagA - CE stimulated PBMCs from PU subjects were significantly higher than the equal cultures from NHS and HIA groups. The CCL22 production by non-stimulated, CagA + CE stimulated and CagA - CE stimulated PBMCs from NHS group were significantly higher than the equal cultures from HIA and PU groups. The CagA + CE stimulated PBMCs from HIA subjects expressed lower amounts of CCR6 in comparison with CagA + CE stimulated PBMCs from NHS and PU groups. The serum levels CXCL10 and CCL20 in PU and HIA groups were significantly higher than NHS subjects. NHS and HIA groups displayed higher serum levels of CCL22 in comparison with PU patients. CONCLUSION: Results indicated that the CagA status of bacterium influence the expression of chemokines and receptors by HP-CE stimulated PBMCs from PU patients.
RESUMO CONTEXTO: Durante a infecção por Helicobacter pylori (HP), a infiltração dos leucócitos na mucosa estomacal é dirigida por quimiocinas produzidas localmente que desempenham um papel decisivo no resultado da infecção. O CagA é o fator de virulência mais potente do HP, de modo que a infecção com cepas CagA + está associada a complicações mais graves do que a infecção com CagA - HP. OBJETIVO: O objetivo foi determinar a expressão das quimiocinas CXCL10, CCL17, CCL20 e CCL22, e seus receptores por CagA + HP- e CagA - extrato bruto (EB) derivado de HP (HP-EB) de células mononucleares do sangue periférico (CMSP) de pacientes com úlcera péptica (UP). MÉTODOS: O soro e as CMSP foram coletados de 20 pacientes com UP infectados pelo HP, 20 indivíduos assintomáticos infectados pelo HP (AI-HP) e 20 indivíduos saudáveis não infectados pelo HP (NI-HP). As CMSP foram cultivadas na ausência de estimulador ou com extrato bruto CagA + HP de 10 μg (CagA + EB), 10 μg CagA - extrato bruto HP (CagA - EB). Quimiocinas e receptores foram medidos por ELISA e PCR em tempo real, respectivamente. RESULTADOS: Em pacientes com UP a produção de quimiocinas CXCL10, CCL17, CCL20 e CCL22, e a expressão dos receptores de quimiocina CXCR3, CCR4 e CCR6 por CagA + CMSP induzidos pelo EB foram significativamente maiores do que as culturas não estimuladas e CagA - EB estimulados. A produção de CXCL10 por CagA + EB estimulou as CMSP de sujeitos AI-HP em proporção significativamente maior do que as culturas iguais dos grupos UP e NI-HP. A produção de CCL17 e CCL20 por grupos não estimulados, CagA + EB estimulado, e CagA - EB estimulou CMSP de sujeitos com UP e foram significativamente superiores às culturas iguais dos grupos NI-HP e AI-HP. A produção de CCL22 por grupos não estimulados, CagA + EB estimulado e CagA - EB estimulado pelo grupo NI-HP foram significativamente maiores do que as culturas iguais dos grupos AI-HP e PU. O CagA + EB estimulou as CMSP dos sujeitos do AI-HP, expressando menores quantidades de CCR6 em comparação com as CMSP estimuladas pelo CagA + EB de grupos NI-HP e UP. Os níveis sanguíneos de CXCL10 e CCL20 nos grupos UP e AI-HP foram significativamente superiores aos dos sujeitos do NI-HP. Os grupos NI-HP e AI-HP apresentaram níveis sanguíneos mais elevados de CCL22 em comparação com pacientes com UP. CONCLUSÃO: Os resultados indicaram que o estado CagA da bactéria influencia a expressão de quimiocinas e receptores por HP-EB estimulados CMSP de pacientes com UP.