RESUMEN
Severe asthma often features a T2 high profile regulated by cytokines such as interleukins IL-4, IL-5 and IL-13. Dupilumab (Dupixent®) is humanized monoclonal antibody directed against the α subunit of the receptor for IL-4 and IL-13. Here we summarise the immunogical background of severe asthma which supports the use of dupilumab and the pivotal randomised controlled trials which have established the efficacy of dupilumab in treating people with severe asthma. Dupilumab reduces the exacerbation rate, has corticosteroids sparing effect, provides sustained improvement in expiratory flow rates and improved asthma control and quality of life with a reassuring safety profile. Dupilumab reduces the levels of FeNO values and of serum IgE but not those of circulating eosinophils. We also report on a few real life data with dupilumab supporting its clinical effectiveness.
L'asthme sévère est souvent caractérisé par un profil immunologique dit «T2 high¼ régulé par des cytokines telles que les interleukines IL-4, IL-5 et IL-13. Le dupilumab (Dupixent®) est un anticorps monoclonal humanisé dirigé contre la sous-unité α du récepteur à l'IL-4 et à l'IL-13. Nous présentons ici les bases immunologiques qui annoncent son efficacité dans le traitement de l'asthme sévère et les grandes études contrôlées qui ont validé son efficacité. Le dupilumab réduit la fréquence des exacerbations, permet une épargne en corticoïdes systémiques, améliore les débits expiratoires, le contrôle de la maladie et la qualité de vie des personnes asthmatiques, sans donner lieu à des effets secondaires notables. Il réduit le taux de FeNO et des IgE sériques, mais pas celui des éosinophiles circulants. Nous donnons également un aperçu de quelques données obtenues en vie réelle pour souligner son utilité en clinique.
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Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Humanos , Interleucina-4/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Interleucina-13/uso terapéutico , Calidad de Vida , Asma/tratamiento farmacológico , Antiasmáticos/farmacología , Antiasmáticos/uso terapéuticoRESUMEN
BACKGROUND: Xiao-Qing-Long-Tang (XQLT), a classical Chinese herbal medicine formula, has been extensively used for allergic asthma treatment. However, there is limited research on its anti-inflammatory effects and mechanisms specifically in neutrophilic asthma (NA). PURPOSE: This study aims to investigate the potential therapeutic effects of XQLT against NA using a combination of network pharmacology and experimental validation. STUDY DESIGN: By utilizing traditional Chinese medicine and disease databases, we constructed an XQLT-asthma network to identify potential targets of XQLT for NA. In the experimental phase, we utilized an ovalbumin (OVA)/lipopolysaccharide (LPS)-induced model for neutrophilic asthma and examined the therapeutic effects of XQLT. RESULTS: Our research identified 174 bioactive components within XQLT and obtained 140 target genes of XQLT against asthma. Functional enrichment analysis revealed that these target genes were primarily associated with inflammation and cytokines. In the experimental validation, mice induced with OVA-LPS showcased eosinophilic and neutrophilic cell infiltration in peri-bronchial areas, elevated levels of IL-4 and IL-17 in both serum and lung, increased percentages of Th2 and Th17 cells in the spleen, as well as elevated levels of CD11b+ and CD103+ dendritic cells (DCs) within the lung. Treatment with XQLT effectively reduced IL-4 and IL-17 levels, decreased the percentages of Th2, Th17, CD11b+, and CD103+ DCs, and improved inflammatory cell infiltrations in lung tissues. These findings serve as a foundation for the potential clinical application of XQLT in neutrophilic asthma.
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Asma , Medicamentos Herbarios Chinos , Interleucina-17 , Ratones , Animales , Interleucina-17/farmacología , Interleucina-17/uso terapéutico , Interleucina-4/farmacología , Interleucina-4/uso terapéutico , Lipopolisacáridos/farmacología , Lipopolisacáridos/uso terapéutico , Farmacología en Red , Asma/tratamiento farmacológico , Pulmón , Citocinas , Ovalbúmina , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad , Líquido del Lavado BronquioalveolarRESUMEN
BACKGROUND: Neuroinflammation induced by systemic inflammation is a risk factor for developing chronic neurologic disorders. Oleuropein (OLE) has antioxidant and anti-inflammatory properties; however, its effect on systemic inflammation-related neuroinflammation is unknown. OBJECTIVES: This study aimed to determine whether OLE protects against systemic lipopolysaccharide (LPS)-induced neuroinflammation in rats. METHODS: Six-wk-old Wistar rats were randomly assigned to 1 of the following 5 groups: 1) control, 2) OLE-only, 3) LPS + vehicle, 4) OLE+LPS (O-LPS), and 5) a single-dose OLE + LPS (SO-LPS group). OLE 200 mg/kg or saline as a vehicle was administered via gavage for 7 d. On the seventh day, 2.5 mg/kg LPS was intraperitoneally administered. The rats were decapitated after 24 h of LPS treatment, and serum collection and tissue dissection were performed. The study assessed astrocyte and microglial activation using glial fibrillary acidic protein (GFAP) and CD11b immunohistochemistry, nod-like receptor protein-3, interleukin (IL)-1ß, IL-17A, and IL-4 concentrations in prefrontal and hippocampal tissues via enzyme-linked immunosorbent assay, and total antioxidant/oxidant status (TAS/TOS) in serum and tissues via spectrophotometry. RESULTS: In both the O-LPS and SO-LPS groups, LPS-related activation of microglia and astrocytes was suppressed in the cortex and hippocampus (P < 0.001), excluding cortical astrocyte activation, which was suppressed only in the SO-LPS group (P < 0.001). Hippocampal GFAP immunoreactivity and IL-17A concentrations in the dentate gyrus were higher in the OLE group than those in the control group, but LPS-related increases in these concentrations were suppressed in the O-LPS group. The O-LPS group had higher cortical TAS and IL-4 concentrations. CONCLUSIONS: OLE suppressed LPS-related astrocyte and microglial activation in the hippocampus and cortex. The OLE-induced increase in cortical IL-4 concentrations indicates the induction of an anti-inflammatory phenotype of microglia. OLE may also modulate astrocyte and IL-17A functions, which could explain its opposing effects on hippocampal GFAP immunoreactivity and IL-17A concentrations when administered with or without LPS.
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Interleucina-17 , Glucósidos Iridoides , Lipopolisacáridos , Ratas , Animales , Masculino , Lipopolisacáridos/toxicidad , Ratas Wistar , Interleucina-17/metabolismo , Interleucina-17/farmacología , Interleucina-17/uso terapéutico , Enfermedades Neuroinflamatorias , Antioxidantes/metabolismo , Interleucina-4/metabolismo , Interleucina-4/farmacología , Interleucina-4/uso terapéutico , Hipocampo/metabolismo , Inflamación/metabolismo , Antiinflamatorios/farmacología , Interleucina-1beta/metabolismo , Microglía/metabolismoRESUMEN
The chemokine receptor CXCR3 is functionally pleiotropic, not only recruiting immune cells to the inflamed liver but also mediating the pathological process of cholestatic liver injury (CLI). However, the mechanism of its involvement in the CLI remains unclear. Both alpha-naphthylisothiocyanate (ANIT) and triptolide are hepatotoxicants that induce CLI by bile acid (BA) dysregulation, inflammation, and endoplasmic reticulum (ER)/oxidative stress. Through molecular docking, CXCR3 is a potential target of ANIT and triptolide. Therefore, this study aimed to investigate the role of CXCR3 in ANIT- and triptolide-induced CLI and to explore the underlying mechanisms. Wild-type mice and CXCR3-deficient mice were administered with ANIT or triptolide to compare CLI, BA profile, hepatic recruitment of IFN-γ/IL-4/IL-17+CD4+T cells, IFN-γ/IL-4/IL-17+iNKT cells and IFN-γ/IL-4+NK cells, and the expression of ER/oxidative stress pathway. The results showed that CXCR3 deficiency ameliorated ANIT- and triptolide-induced CLI. CXCR3 deficiency alleviated ANIT-induced dysregulated BA metabolism, which decreased the recruitment of IFN-γ+NK cells and IL-4+NK cells to the liver and inhibited ER stress. After triptolide administration, CXCR3 deficiency ameliorated dysregulation of BA metabolism, which reduced the migration of IL-4+iNKT cells and IL-17+iNKT cells and reduced oxidative stress through inhibition of Egr1 expression and AKT phosphorylation. Our findings suggest a detrimental role of CXCR3 in ANIT- and triptolide-induced CLI, providing a promising therapeutic target and introducing novel mechanisms for understanding cholestatic liver diseases.
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1-Naftilisotiocianato , Colestasis , Diterpenos , Fenantrenos , Animales , Ratones , 1-Naftilisotiocianato/toxicidad , 1-Naftilisotiocianato/metabolismo , Interleucina-17/toxicidad , Interleucina-17/metabolismo , Interleucina-17/uso terapéutico , Interleucina-4/toxicidad , Interleucina-4/metabolismo , Interleucina-4/uso terapéutico , Simulación del Acoplamiento Molecular , Hígado/metabolismo , Colestasis/inducido químicamente , Ácidos y Sales Biliares , Compuestos EpoxiRESUMEN
PURPOSE: The purpose of this study was to test the hypothesis that brain white matter hyperintensities (WMH) are more common in patients receiving epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and identify clinical risk factors associated with WMH. EXPERIMENTAL DESIGN: This multiple-center, prospective cohort study was conducted from March 2017 to July 2020. Two groups of patients with non-small cell lung cancer (NSCLC) who received or did not receive EGFR-TKI were included and followed up for more than 24 months. The progression of WMH was defined as an increase of ≥1 point on the Fazekas visual rating scale between the baseline and at the 2-year follow-up. A modified Poisson regression model was performed to evaluate risk factors on increased WMH load. RESULTS: Among 286 patients with NSCLC, 194 (68%) patients with NSCLC who received EGFR-TKI and 92 (32%) patients with NSCLC without EGFR-TKI treatment were analyzed. Modified Poisson regression analysis showed that EGFR-TKI treatment was independently associated with the WMH progression (EGFR-TKI: aRR 2.72, 95% confidence interval [CI] 1.46-5.06, p = .002). Interleukin (IL)-2, IL-4, and IL-10 were associated with increased WMH in the adjusted model (IL-2: aRR 1.55 [95% CI 1.06-2.25], p = .023; IL-4: aRR 1.66 [95% CI 1.13-2.43], p = .010; IL-10: aRR 1.48 [95% CI 1.06-2.06], p = .020). CONCLUSION: Patients with NSCLC who received EGFR-TKI may be at higher risk of developing WMH or worsening of WMH burden. The impact of increased WMH lesions in these patients is to be further assessed. IL-2, IL-4, and IL-10 may be used as potential biomarkers to monitor the risk of increased WMH burden.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Sustancia Blanca , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Interleucina-2 , Interleucina-10 , Estudios Prospectivos , Interleucina-4/uso terapéutico , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Mutación , Estudios RetrospectivosRESUMEN
Atopic dermatitis (AD) is a common skin disease involving important immune mechanisms. There is an unmet need for a treatment for this condition. Herein, we focused on elucidating the role of Bi2-xMnxO3 nanospheres (BM) in alleviating skin inflammation in AD-like C57BL/6 mice. The BM was fabricated via sacrificial templates and its biosafety was systematically evaluated. The BM was applied topically to skin lesions of AD-like C57BL/6 mice. The phenotypic and histological changes in the skin were examined carefully. The responses of barrier proteins, inflammatory cytokines and cells to BM were evaluated in HaCaT cells and AD mouse models. The data demonstrated that BM treatment alleviated the AD phenotypes and decreased the level of inflammatory factors, while increasing the expression of the barrier proteins filaggrin/involucrin in the skin. BM effectively reduced the expression of phosphorylated STAT6, which in turn reduced the expression of GATA3, and further decreased the differentiation ratio of Th2 cells, thereby reducing the expression of IL-4. In conclusion, topical drug therapy with BM provides a safe and effective treatment modality for AD by reducing IL-4 and increasing barrier proteins.
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Dermatitis Atópica , Nanosferas , Ratones , Animales , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Manganeso/farmacología , Interleucina-4/metabolismo , Interleucina-4/farmacología , Interleucina-4/uso terapéutico , Ratones Endogámicos C57BL , Piel , Inflamación/patología , Citocinas/metabolismoRESUMEN
In 2017, dupilumab became the first FDA approved systemic therapy for atopic dermatitis. Since its approval, extensive clinical experience and continued research have revealed a number of unexpected effects that are highly clinically relevant. We will review these clinical effects and the supporting evidence.J Drugs Dermatol. 2023;22(10):1007-1008 doi:10.36849/JDD.7249.
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Anticuerpos Monoclonales , Dermatitis Atópica , Humanos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Interleucina-13/uso terapéutico , Interleucina-4/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: This study examined (a) whether there are a subgroup of cancer patients experiencing the selected psycho-neurological symptoms as a cluster (depression, cognitive impairment, fatigue, sleep disturbance, and pain); (b) whether demographic and clinical characteristics and pro-inflammatory cytokines (IL-1α, IL-1ß, IL-4, IL-6, TNF-alpha) are associated with subgroup membership; and (c) whether the activity of indolamine-2.3 dioxygenase(IDO) is associated with pro-inflammatory cytokine activity and psycho-neurological symptom cluster experience. METHODS: This was a prospective cohort study where 149 hematologic patients were recruited from a university hospital and 65 healthy volunteers provided control data. Latent profile analyses were conducted to identify subgroups at two time points: the last day of chemotherapy and 1 week after chemotherapy completion. Influencing factors of subgroup membership were examined by logistic regression. RESULTS: A substantial number of patients (33%, 34% at each time point) experienced the selected psycho-neurological symptoms as a cluster. Older age and elevated IL-1α and IL-6 were associated with experiencing the psycho-neurological symptom cluster. IDO activity was higher in the patients experiencing psycho-neurological symptom cluster; and was positively associated with IL-6. Symptom severity, IL-1α, IL-6, and IDO activity were all significantly higher in cancer patients than in the healthy controls. The findings were preserved across time points. CONCLUSIONS: The activation of pro-inflammatory cytokines and their cross-talk with IDO may be a common biological mechanism, underlying a psycho-neurological symptom cluster experience. The novel approaches for symptom assessment and management can be developed by assessing multiple psycho-neurological symptoms as a cluster and by targeting their common biological pathway.
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Dioxigenasas , Neoplasias Hematológicas , Neoplasias , Humanos , Triptófano/metabolismo , Triptófano/uso terapéutico , Quinurenina/metabolismo , Citocinas , Factor de Necrosis Tumoral alfa , Interleucina-6 , Interleucina-4/uso terapéutico , Síndrome , Estudios Prospectivos , Neoplasias/psicologíaRESUMEN
The objective of this study was to observe the effect of recombinant human thrombopoietin on IL-2, IL-4 and platelet parameters in thrombocytopenic purpura. For this purpose, a convenient sampling method was used to select 84 patients with thrombocytopenic purpura who visited the hospital from January 2018 to December 2022. The patients were divided into the norm group and rhTPO group with 42 cases each by random number table. The norm group was treated with routine treatment, while the rhTPO group was treated with recombinant thrombopoietin based on routine treatment. The changes in IL-2, IL-4, platelet parameters, immune recovery and treatment efficiency of the two groups were compared before and after treatment. Findings suggested that the levels of IL-2 and IL-4 in both groups decreased after treatment compared with those before treatment. However, the level of IL-2 in the rhTPO group after treatment was lower than that in the norm group, and the level of IL-4 in the rhTPO group after treatment was higher than that in the norm group (P<0.05). The levels of platelet parameters PLT and PCT in the two groups after treatment were higher than those before treatment, but the levels of PLT and PCT in the rhTPO group after treatment were higher than those in the norm group (P<0.05). The PLT of the rhTPO group was (69.57±6.73)×109/L after 7 days of treatment, which was higher than that in the norm group (62.05 ± 8.52)×109/L (P<0.05). The levels of PDW and MPV in the two groups after treatment decreased compared with those before treatment, but the levels of PDW and MPV in the rhTPO group after treatment were lower than those in the norm group (P<0.05). The overall immune recovery and treatment effectiveness of the rhTPO group were significantly better than those of the norm group. In summary, recombinant human thrombopoietin used in patients with thrombocytopenic purpura can maintain the balance between T cell activation and inhibition homeostasis, and promote faster recovery of platelet parameters.
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Púrpura Trombocitopénica Idiopática , Humanos , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Trombopoyetina/uso terapéutico , Interleucina-2/uso terapéutico , Interleucina-4/uso terapéutico , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéuticoRESUMEN
Objective: This study aimed to explore the correlation of serum ATG5 levels with the disease risk, Th2/Th1 imbalance, symptoms and therapeutic outcomes of allergic rhinitis (AR) patients. Methods: Serum ATG5 levels in 160 AR patients, 30 disease controls and 30 healthy controls were measured by ELISA. AR patients received oral antihistamine, intranasal corticosteroid, leukotriene receptor antagonist monotherapy or their combination as needed for 4 weeks. Results: AR patients had elevated ATG5 levels compared with disease controls and healthy controls (p < 0.001). In AR patients, ATG5 levels were positively correlated with total nasal symptom scores, IL-4 levels and the IL-4/IFN-γ axis (all p < 0.05); the reduction in the ATG5 level was positively related to the total nasal symptom score decline from week 0 to week 4 (p = 0.038). Conclusion: Serum ATG5 levels have diagnostic and disease-monitoring value in AR management due to their relationship with Th2 cells and symptoms.
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Rinitis Alérgica , Células Th2 , Humanos , Animales , Interleucina-4/uso terapéutico , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/tratamiento farmacológico , Resultado del Tratamiento , Citocinas , Modelos Animales de Enfermedad , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/uso terapéuticoRESUMEN
Little is known about whether type 1 (IFNγ), 2 (IL-4/IL-13), or 3 (IL-17A/IL-22) cytokines affect the susceptibility of keratinocytes (KC) to viruses. These immune pathways predominate in various skin diseases: lupus, atopic dermatitis (AD), and psoriasis, respectively. Janus kinase inhibitors (JAKi) are approved to treat both AD and psoriasis, and are in clinical development for lupus. We evaluated whether these cytokines alter viral susceptibility of KC and determined if this effect is modulated by treatment with JAKi. Viral susceptibility to vaccinia virus (VV) or herpes simplex virus-1 (HSV-1) ± JAKi was assessed in immortalized and primary human KC pretreated with cytokines. Exposure to type 2 (IL-4 + IL-13) or the type 3 (IL-22) cytokines significantly increased KC viral susceptibility. Specifically, there was a peak increase of 12.2 ± 3.1-fold (IL-4 + IL-13) or 7.7 ± 2.8-fold (IL-22) in VV infection as measured by plaque number. Conversely, IFNγ significantly reduced susceptibility to VV (63.1 ± 64.4-fold). The IL-4 + IL-13-induced viral susceptibility was reduced (44 ± 16%) by JAK1 inhibition, while the IL-22-enhanced viral susceptibility was diminished (76 ± 19%) by TYK2 inhibition. IFNγ-mediated resistance to viral infection was reversed by JAK2 inhibition (366 ± 294% increase in infection). Cytokines expressed in AD skin (IL-4, IL-13, IL-22) increase KC viral susceptibility while IFNγ is protective. JAKi that target JAK1 or TYK2 reversed cytokine-enhanced viral susceptibility, while JAK2 inhibition reduced the protective effects of IFNγ.
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Dermatitis Atópica , Inhibidores de las Cinasas Janus , Psoriasis , Humanos , Citocinas/metabolismo , Interleucina-13/farmacología , Interleucina-4/farmacología , Interleucina-4/uso terapéutico , Queratinocitos/metabolismo , Psoriasis/tratamiento farmacológico , Dermatitis Atópica/tratamiento farmacológico , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Virus Vaccinia/fisiologíaRESUMEN
Cancer metastasis remains the most common cause of death in breast cancer patients. Tumor-associated macrophages (TAMs) are a novel therapeutic target for the treatment of metastatic breast cancer. Despite the good anti-cancer activity of garcinone E (GE), there are no reports on its therapeutic effects on breast cancer metastasis. The objective of this study was to examine the anti-cancer effects of GE on metastatic breast cancer. RAW 264.7 and THP-1 cells were polarized to M2 macrophages by IL-4/IL-13 in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were used to explore the effect of GE on breast cancer growth and metastasis in vivo. In vitro studies showed that GE dose-dependently suppressed IL-4 + IL-13-induced expression of CD206 in both RAW 264.7 cells and differentiated THP-1 macrophages. However, GE did not affect the LPS + IFN-γ-induced polarization to the M1-like macrophages in vitro. GE inhibited the expression of the M2 macrophage specific genes in RAW 264.7 cells, and simultaneously impaired M2 macrophage-induced breast cancer cell proliferation and migration, and angiogenesis. In animal studies, GE significantly suppressed tumor growth, angiogenesis, and lung metastasis in 4T1 tumor-bearing mice, without causing toxicity. In both tumor and lung tissues, the proportion of M2-like TAMs was significantly decreased while the proportion of M1-like TAMs was markedly increased by GE treatment. Mechanistically, GE inhibited phosphorylation of STAT6 in vitro and in vivo. Our results demonstrate for the first time that GE suppresses breast cancer growth and pulmonary metastasis by modulating M2-like macrophage polarization through the STAT6 signaling pathway.
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Neoplasias de la Mama , Humanos , Animales , Ratones , Femenino , Neoplasias de la Mama/patología , Macrófagos Asociados a Tumores , Línea Celular Tumoral , Interleucina-4/metabolismo , Interleucina-4/farmacología , Interleucina-4/uso terapéutico , Interleucina-13/metabolismo , Interleucina-13/farmacología , Interleucina-13/uso terapéutico , Transducción de Señal , Factor de Transcripción STAT6/metabolismo , Factor de Transcripción STAT6/farmacologíaRESUMEN
Periodontal bone regeneration is a major challenge in the treatment of periodontitis. Currently the main obstacle is the difficulty of restoring the regenerative vitality of periodontal osteoblast lineages suppressed by inflammation, via conventional treatment. CD301b+ macrophages were recently identified as a subpopulation that is characteristic of a regenerative environment, but their role in periodontal bone repair has not been reported. The current study indicates that CD301b+ macrophages may be a constituent component of periodontal bone repair, and that they are devoted to bone formation in the resolving phase of periodontitis. Transcriptome sequencing suggested that CD301b+ macrophages could positively regulate osteogenesis-related processes. In vitro, CD301b+ macrophages could be induced by interleukin 4 (IL-4) unless proinflammatory cytokines such as interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were present. Mechanistically, CD301b+ macrophages promoted osteoblast differentiation via insulin-like growth factor 1 (IGF-1)/thymoma viral proto-oncogene 1 (Akt)/mammalian target of rapamycin (mTOR) signaling. An osteogenic inducible nano-capsule (OINC) consisting of a gold nanocage loaded with IL-4 as the "core" and mouse neutrophil membrane as the "shell" was designed. When injected into periodontal tissue, OINCs first absorbed proinflammatory cytokines in inflamed periodontal tissue, then released IL-4 controlled by far-red irradiation. These events collectively promoted CD301b+ macrophage enrichment, which further boosted periodontal bone regeneration. The current study highlights the osteoinductive role of CD301b+ macrophages, and suggests a CD301b+ macrophage-targeted induction strategy based on biomimetic nano-capsules for improved therapeutic efficacy, which may also provide a potential therapeutic target and strategy for other inflammatory bone diseases.
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Regeneración Ósea , Interleucina-4 , Periodontitis , Animales , Ratones , Citocinas/metabolismo , Interleucina-4/farmacología , Interleucina-4/metabolismo , Interleucina-4/uso terapéutico , Macrófagos/fisiología , Mamíferos , Osteogénesis , Periodontitis/tratamiento farmacológicoRESUMEN
BACKGROUND: Periodontitis has a high prevalence and uncertain recurrence. Unlike the pro-inflammatory cytokine profile, little is known about the anti-inflammatory cytokine and antimicrobial peptide overview following treatment. The present study aimed to evaluate if any of the antimicrobial peptide LL-37, interleukin (IL) 4, 10 and 6 together with the volume of gingival crevicular fluid (GCF) and total protein concentration in GCF could be used as correlative biomarkers for the severity in periodontitis as well as prognostic factors in the management of the disease. METHODS: Forty-five participants were recruited and allocated to the healthy (15), Stage I-II (15) or Stage III-IV periodontitis (15) group. Along with periodontal examination, GCF samples were obtained at baseline and 4-6 weeks following scaling and root planing (SRP) for the periodontitis groups. GCF samples were analyzed by ELISA kits to quantify LL-37 and IL-4, -6 and - 10. One-way ANOVA followed by Dunnett's test was used to determine differences among the three groups at baseline. Two-way ANOVA followed by Sidak's post-hoc test was used to compare between pre- and post-SRP in the two periodontitis groups. RESULTS: The amount of GCF volume was significantly correlated to the severity of periodontitis and decreased following SRP, particularly in the Stage III-IV group (p < 0.01). The levels of LL-37, IL-6, and pain and periodontal clinical parameters were significantly correlated to the severity of periodontitis. IL-4 and IL-10 in the periodontitis groups were significantly lower than the healthy group (p < 0.0001) and barely improved following SRP up to the level of the healthy group. CONCLUSIONS: With the limitations of this study, crevicular LL-37 may be a candidate for a biomarker of periodontitis and the associated pain upon probing. TRIAL REGISTRATION: The study was registered in clinical trials.gov, with number NCT04404335, dated 27/05/2020.
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Catelicidinas , Periodontitis , Humanos , Catelicidinas/uso terapéutico , Interleucina-4/uso terapéutico , Proyectos Piloto , Péptidos Antimicrobianos , Periodontitis/terapia , Aplanamiento de la Raíz , Raspado Dental , Líquido del Surco GingivalRESUMEN
Graft-versus-host disease (GVHD) is the major factor limiting the widespread use of potentially curative allogeneic hematopoietic stem cell transplant (allo-HSCT). Chronic GVHD is characterized by the activation of alloreactive donor immune cells, especially B- and T-cells, leading to tissue damage and pathogenic fibrosis. In this study, we used highly specific next-generation inhibitors of ITK (PCYC-274), BTK (PCYC-804), and ibrutinib-like BTK/ITK inhibitors (PCYC-914 and PCYC-401) in the B10.D2 â BALB/C model of murine sclerodermatous cGVHD. From the third week onward, allogeneic recipients in each group of respective Tec kinase inhibitors were treated three times weekly with inhibitors at doses of 10 and 30 mg/kg or with saline control via oral gavage. Overall, we found that selective BTK inhibition was less effective than combined ITK/BTK or ITK inhibition in lengthening survival and reducing symptoms of cGVHD. ITK inhibition was most efficacious, with PCYC-274 and PCYC-401 demonstrating a nearly 50 percent reduction in GVHD scoring even at the 10 mg/kg dose, while 30 mg/kg of these compounds almost completely ameliorated GVHD symptomology. BTK/ITK and ITK-treated mice showed significant reductions in overall pathology. Significant reductions in dermal thickness and fibrosis were shown for all treatment groups. There was evidence of mixed Th1 and Th2 cytokine profiles in the skin of mice with dermal cGVHD, as both IFN-gamma and IL-4 were upregulated in the allogeneic control group, while kinase inhibition significantly reduced levels of these cytokines. Using an in vitro model of T-cell polarization, Th1 cell production of TNF-alpha and IFN-gamma were partially blocked by ITK. Th2 cell production of IL-4 was almost completely blocked synergistically by ITK and BTK inhibition. BTK-specific inhibition was unable to block either Th1 or Th2 cytokine production. Taken together, these results confirm previous reports that ITK-focused inhibition inhibits Th1 and Th2 cells. Additionally, the compound's effects on T-cell proliferation were tested by CFSE assay. Pure ITK inhibition was most effective at blocking T-cell proliferation, with no proliferation in PCYC-274-treated cells even at 0.1uM. PCYC-401 and PCYC-914 showed some inhibition at lower doses, with complete inhibition evident at 10uM. PCYC-804 was only partially able to block proliferation even at 10uM. In conclusion, we observed substantial benefit for differential inhibition of Tec kinases in GVHD, with ITK being most efficacious and Th1 cells being more resistant to inhibition, matching the previously reported findings of a Th2 to Th1 selective pressure in cells treated with ibrutinib. Our data warrants the further development of ITK and ITK/BTK inhibitors with specific inhibitory ratios to improve the treatment of GVHD and other T-cell mediated diseases.
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Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Animales , Ratones , Interleucina-4/uso terapéutico , Ratones Endogámicos BALB C , Citocinas , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/patología , FibrosisRESUMEN
OBJECTIVE: To characterize the presentation and outcomes of patients with atopic dermatitis (AD) who developed musculoskeletal symptoms after treatment with dupilumab, a human IgG4 monoclonal antibody that blocks the functions of interleukin-4 (IL-4) and IL-13, key pathologic pathways in AD. METHODS: This article reports an observational cohort of patients receiving dupilumab who developed new-onset musculoskeletal symptoms after dupilumab therapy at our center. All patients had a comprehensive rheumatologic history and examination, with imaging by ultrasonography (US) or magnetic resonance imaging (MRI) in most patients. RESULTS: Between October 2018 and February 2021, we recorded 470 patients with AD commencing dupilumab treatment from routine clinical care records. Of 36 patients referred for rheumatologic assessment, we identified 26 patients (14 male, 12 female) with a musculoskeletal syndrome of inflammatory enthesitis, arthritis, and/or tenosynovitis. Clinical findings were confirmed by US and MRI. All patients had very good response to dupilumab treatment, and no specific predictors of musculoskeletal syndrome were noted. Symptoms were mild in 16 patients, moderate in 6 patients, and severe in 4 patients. Receipt of nonsteroidal antiinflammatory drugs or cyclooxygenase 2 inhibitors, reduction of dupilumab dose/frequency, and cessation of dupilumab therapy led to improvement, but moderate or severe symptoms persisted for many months. CONCLUSION: We report a new musculoskeletal syndrome of inflammatory enthesitis/arthritis/tenosynovitis in some patients receiving the IL-4 receptor antagonist dupilumab. This response to a cytokine-targeting therapy provides key insights into the pathogenesis of enthesitis.
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Artritis Reumatoide , Dermatitis Atópica , Tenosinovitis , Humanos , Masculino , Femenino , Dermatitis Atópica/complicaciones , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/diagnóstico , Interleucina-4/uso terapéutico , Inhibidores de Interleucina , Resultado del Tratamiento , Índice de Severidad de la EnfermedadRESUMEN
Aim: Bullous pemphigoid (BP) is an organ-specific autoimmune bullous disease characterized by autoantibodies that target the cellular adhesion molecules BP180 and BP230. Both immunoglobulin (Ig)G and IgE are involved in the induction of subepidermal blisters. Specifically, IgE autoantibodies are presumed to be responsible for the pruritic and erythematous features of BP. Histologically, eosinophil infiltration is a prominent feature in BP. Eosinophils and IgE are mostly associated with the Th2 immune response. Th2 cytokines, particularly interleukin (IL)-4 and IL-13, are presumed to contribute to the pathology of BP. The aim of this review is to discuss the role of IL-4/13 in the pathogenesis of BP and the potential of using IL-4/13 antagonists for treatment.Methods: After searching in PubMed and Web of Science databases using 'bullous pemphigoid', 'interleukin-4/13', and 'dupilumab' as keywords, studies related was compiled and examined.Results: Overall, IgE, eosinophils, IL-4, and IL-13 may interact with each other in the pathogenesis of BP; these potential interactions provide clues concerning targets for molecular treatment.Conclusion: Anti-IL-4/13 treatment has been experimentally used in patients with BP, with satisfactory outcomes and few side effects. However, before this novel therapy can be approved for regular usage, further studies are needed concerning the long-term safety and systemic usage of IL-4/13 monoclonal antibody treatment in BP.KEY MESSAGESBP is an autoimmune skin disease with Th2-mediated autoimmune response involvement.As typical Th2 cytokines, IL-4 and IL-13 may contribute to the pathogenesis of BP in multiple ways, such as promoting Th2 cell polarization, driving the immunoglobulin class switching, recruiting eosinophils and basophils, and inducing pruritus.As a promising therapeutic approach for BP, IL-4/13 antagonists have shown satisfactory outcomes in preliminary clinical studies.
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Penfigoide Ampolloso , Humanos , Penfigoide Ampolloso/tratamiento farmacológico , Interleucina-13/uso terapéutico , Inmunoglobulina E , Interleucina-4/uso terapéutico , Inmunoglobulina G , Citocinas/uso terapéutico , Autoanticuerpos , AutoantígenosRESUMEN
Interleukin-4 (IL-4) is a pleiotropic cytokine mainly known for its role in type 2 immunity. Therapies antagonizing or blocking IL-4 activity have been developed to counteract diseases such as atopic dermatitis and asthma. In contrast, other disorders experimentally benefit from IL-4-related effects and IL-4 recently demonstrated beneficial activity in experimental stroke, spinal cord injury and the animal model of multiple sclerosis. To exploit IL-4-related activity for therapeutic concepts, current experimental efforts include modifying the pathway without inducing type 2 immune response and targeting of the cytokine to specific tissues. Here, we review different activities of IL-4 as well as therapeutic strategies.
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Asma , Dermatitis Atópica , Animales , Asma/tratamiento farmacológico , Citocinas , Dermatitis Atópica/tratamiento farmacológico , Interleucina-33 , Interleucina-4/uso terapéutico , HumanosRESUMEN
Immune-mediated hypersensitivities such as autoimmunity, allergy, and allogeneic graft rejection are treated with therapeutics that suppress the immune system, and the lack of specificity is associated with significant side effects. The delivery of disease-relevant antigens (Ags) by carrier systems such as poly(lactide-co-glycolide) nanoparticles (PLG-Ag) and carbodiimide (ECDI)-fixed splenocytes (SP-Ag) has demonstrated Ag-specific tolerance induction in model systems of these diseases. Despite therapeutic outcomes by both platforms, tolerance is conferred with different efficacy. This investigation evaluated Ag loading and total particle dose of PLG-Ag on Ag presentation in a coculture system of dendritic cells (DCs) and Ag-restricted T cells, with SP-Ag employed as a control. CD25 expression was observed in nearly all T cells even at low concentrations of PLG-Ag, indicating efficient presentation of Ag by dendritic cells. However, the secretion of IL-2, Th1, and Th2 cytokines (IFNγ and IL-4, respectively) varied depending on PLG-Ag concentration and Ag loading. Concentration escalation of soluble Ag resulted in an increase in IL-2 and IFNγ and a decrease in IL-4. Treatment with PLG-Ag followed a similar trend but with lower levels of IL-2 and IFNγ secreted. Transcriptional Activity CEll ARrays (TRACER) were employed to measure the real-time transcription factor (TF) activity in Ag-presenting DCs. The kinetics and magnitude of TF activity was dependent on the Ag delivery method, concentration, and Ag loading. Ag positively regulated IRF1 activity and, as carriers, NPs and ECDI-treated SP negatively regulated this signaling. The effect of Ag loading and dose on tolerance induction were corroborated in vivo using the delayed-type hypersensitivity (DTH) and experimental autoimmune encephalomyelitis (EAE) mouse models where a threshold of 8 µg/mg Ag loading and 0.5 mg PLG-Ag dose were required for tolerance. Together, the effect of Ag loading and dosing on in vitro and in vivo immune regulation provide useful insights for translating Ag-carrier systems for the clinical treatment of immune disorders.
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Encefalomielitis Autoinmune Experimental , Nanopartículas , Animales , Ratones , Linfocitos T , Interleucina-2 , Interleucina-4/uso terapéutico , Antígenos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológicoRESUMEN
Inflammation-related diseases are recognized as the major cause of morbidity around the globe. In this study, the anti-inflammatory potential of sericin, curcumin, and their mixture was investigated in vivo and in vitro. Edema was induced via 1% carrageenan and then sericin (0.03, 0.06, 0.09 mg/ml), curcumin (1%, 2%, 3%), and their mixture doses were applied topically. The paw circumference and thickness were measured after 1-, 2-, 3-, 4-, 5-, and 6-hour post-carrageenan injection. The levels of IL-4 and IL-10 were measured from the serum. In mice fibroblast cells, sericin (20, 40, 60 µg/ml), curcumin (5, 10, 20 µM), and mixture concentrations were applied and then stimulated with lipopolysaccharide (LPS). Afterward, the cells were used for the analysis of gene expression, and the supernatant was collected for protein expression of IL-1ß, IL-4, and IL-10. Our results demonstrated that sericin and curcumin caused a dose-dependent reduction in edema, whereas the mixture-treated group reduced the paw thickness and circumference most significantly (p = .0001). Furthermore, the mixture treatment of carrageenan-inflicted group increased the levels of anti-inflammatory cytokines, IL-4 (650.87 pg/ml) and IL-10 (183.14 pg/ml), in comparison to the carrageenan control. The in vitro data revealed that among all the treatment doses, the mixture-treated group has effectively reduced the gene (1.13-fold) and protein (51.9 pg/ml) expression of IL-1ß in comparison to McCoy cells stimulated with LPS. Moreover, mixture treatment elevated the expression of IL-4 and IL-10 at genes (4.3-fold and 3.7-fold, respectively) and protein levels (169.33 and 141.83 pg/ml, respectively). The current study reports the enhanced anti-inflammatory effects of the mixture of curcumin and sericin through modulating expressions of interleukins in vitro and in vivo. Thus, natural products (curcumin and sericin)-based formulations have greater potential for clinical investigations.