Inhibitory effect of Zingiber cassumunar Roxb. (Phlai) on nasal cytokine productions and eosinophilic recruitment in patients with allergic rhinitis.

BACKGROUND: Zingiber cassumunar Roxb. (Phlai) has been used for the treatment of allergies including allergic rhinitis (AR). Although the anti-histamine effects have been reported, assessment of nasal cytokine and eosinophil production had not been investigated. OBJECTIVE: This study aimed to examine the effect of Phlai on alterations in nasal pro-inflammatory cytokine levels and eosinophil counts in nasal mucosa. METHODS: This was a randomized, double-blind, three-way crossover study. Nasal concentrations of cytokines, namely interleukin (IL)-4, IL-5, IL-13 and interferron-gamma (IFN-γ), nasal smear eosinophilia as well as total nasal symptom score (TNSS) were evaluated before and after a 4 weeks treatment with 200 mg Phlai capsules or placebo in 30 AR patients. RESULTS: We observed significant (p < 0.05) reduction in IL-5, IL-13 as well as the number of eosinophils in subjects given Phlai. The degree of improvement of TNSS after Phlai treatment was initially manifested in week 2 with the greatest effect in week 4. In contrast, there were no significant differences in all nasal cytokines, eosinophil counts or TNSS between before and after receiving placebo. CONCLUSIONS: These findings provided the first evidence for the anti-allergic effect of Phlai which possibly involved inhibition of nasal pro-inflammatory cytokines production and eosinophilic recruitment. Phlai thus represents a promising herbal medicine for alleviating inflammation and AR symptoms.

Targeting the interleukin-5 pathway in EGPA: evidence, uncertainties and opportunities.

Only a minority of patients with eosinophilic granulomatosis with polyangiitis (EGPA) can be weaned-off glucocorticoids (GC) using conventional treatment strategies. The development of biological agents specifically inhibiting the IL-5 pathway provided the opportunity to treat EGPA by targeting one of the crucial regulators of eosinophils, reducing the GC dose required to control the disease.The anti-IL-5 antibody mepolizumab at the dose of 300 mg/4 weeks has proven to be safe and effective in EGPA. While relapsing patients-who often experience recurrent respiratory manifestations-benefit from this treatment, data are not enough to support its use combined with GC alone in remission induction of severe active forms, or in remission maintenance without conventional immunosuppressants in patients with vasculitic manifestations. Ultimately, the profile of the best candidate for mepolizumab is still unclear.Several real-life reports suggest that mepolizumab at the dose of 100 mg/4 weeks, approved for eosinophilic asthma/chronic rhinosinusitis with nasal polyposis (CRSwNP), effectively maintains remission of EGPA-related asthma and, to a lesser extent, CRSwNP. Preliminary data on the IL-5 pathway-inhibitors benralizumab and reslizumab in EGPA as steroid-sparing agents are also accumulating.Overall, it remains to be proven whether targeting the IL-5 pathway could block progression of organ damage in EGPA, on top of reducing relapses and sparing GC. Other disease-related factors further complicate the understanding of the real anti-IL-5 agent efficacy, such as the lack of a clear definition of remission, of an effective tool to measure disease activity, and of well-defined treat-to-target approaches or goals of treatment.

Preclinical development of a long-acting trivalent bispecific nanobody targeting IL-5 for the treatment of eosinophilic asthma.

BACKGROUND: Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence. RESULTS: We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability. CONCLUSIONS: These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma.

A Phase 1 study of the long-acting anti-IL-5 monoclonal antibody GSK3511294 in patients with asthma.

AIMS: GSK3511294 is a humanized anti-interleukin (IL)-5 monoclonal antibody (mAb) engineered for extended half-life and improved IL-5 affinity versus other anti-IL-5 mAbs. This study examined its safety, tolerability, pharmacokinetics (PK) and effect on blood eosinophil counts. METHODS: This was a double-blind, parallel-group, single-ascending-dose, multicenter, Phase 1 study (205 722;NCT03287310) in patients with asthma and a blood eosinophil count ≥200 cells µL-1 . Patients were randomized 3:1 within dose cohorts to receive a single subcutaneous dose of GSK3511294 (2, 10, 30, 100 or 300 mg) or placebo and followed for up to 40 weeks to assess safety (primary endpoint), ratio to baseline in blood eosinophil count, plasma PK parameters and frequency/titers of binding antidrug antibodies (all secondary). RESULTS: Forty-eight patients received the study drug and completed the study. Adverse events (AEs) occurred in 92% of placebo-treated and 81% of GSK3511294-treated patients. There were no AEs leading to study withdrawal or serious AEs; hypersensitivity (one event in one patient) and injection-site reaction (three events in two patients) occurred infrequently. Marked reductions (>48%) in blood eosinophil count were seen from 24 hours post-dose with all GSK3511294 doses but not placebo; suppression was maintained for longer with increasing dose (82% and 83% adjusted reductions vs placebo with 100 and 300 mg, respectively, at week 26). PK were linear and dose proportional over the dose range; terminal half-life was 38-53 days. CONCLUSIONS: GSK3511294 was well tolerated, with linear and dose proportional PK, extended half-life and blood eosinophil count reduction, supporting less frequent dosing versus other anti-IL-5 mAbs.

World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary or clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109 /L. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, next generation sequencing gene assays, and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2", and the myeloproliferative neoplasm subtype, "chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant HE is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (eg, < 1.5 × 109 /L) without symptoms or signs of organ involvement, a watch and wait approach with close follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. Mepolizumab, an interleukin-5 (IL-5) antagonist monoclonal antibody, was recently approved by the US Food and Drug Administration for patients with idiopathic HES. The use of the IL-5 receptor antibody benralizumab, as well as other targeted therapies such as JAK2 and FGFR1 inhibitors, is under active investigation.

The clinical differences between cough variant asthma cells and humoral immunology indicators.

The Purpose of this study was to study and analyze the clinical differences between cough variant asthma (CVA) cells and humoral immunology indicators. For this aim, 73 sick children with CVA were enrolled in this study and were admitted to the Pediatric Inpatient Department of Weifang Maternal and Child Health Hospital for treatment from April 2019 to May 2021. They were divided into the attack stage group (n=45) and the remission stage group (n=28). Meanwhile, 30 children with normal physical examination results were selected as normal controls. Differences in serum levels of TNF-, hs-CRP, IL-4, IL-5, IL-6 and IL-13 were compared among the three groups, as well as the differences in humoral immunology indicators such as T lymphocyte subsets CD3+, CD4+, CD8+, CD4+/ CD8+ and IgA, IgG, IgG, IgM, IgE, IgE and IgG subtypes. Results showed that serum levels of TNF-α and hs-CRP were significantly higher in the attack stage group than those in the remission stage group and normal control group, and the difference was statistically significant (P<0.05). The serum levels of TNF-α and hs-CRP were higher in the remission stage group than those in the normal control group, and the difference was not statistically significant (P>0.05). Serum levels of IL-4, IL-5, IL-6 and IL-13 were significantly higher in the attack stage group than those in the remission stage group and normal control group, and the difference was statistically significant (P<0.05). CD4+ and CD4+/CD8+ were significantly higher in the attack stage group than those in the remission stage group and normal control group, and the difference was statistically significant (P<0.05). The difference in serum levels of IgG1, IgG2 and IgG3 was not statistically significant (P>0.05) among the three groups. While the level of IgG4 subsets in the attack stage group was significantly higher than that in the remission stage group and normal control group, and the difference was statistically significant (P<0.05). Then the cytokines, cells and humoral immunology indicators of CVA patients are not in their normal range. They are involved in the pathogenesis of CVA. The combined detection is of great clinical significance in the diagnosis of early CVA to avoid misdiagnosis and missed diagnosis.

Time-dependent dual beneficial modulation of interferon-γ, interleukin 5, and Treg cytokines in asthma patient peripheral blood mononuclear cells by ganoderic acid B.

Th2 cytokines play a dominant role in the pathogenesis of allergic asthma. Interferon gamma (IFN-γ), a Th1 cytokine, links to therapeutic mechanisms of allergic asthma. Interleukin (IL)-10, a regulatory cytokine, is involved in the induction of immune tolerance. We previously demonstrated that Anti-Asthma Simplified Herbal Medicine Intervention (ASHMI) suppressed Th2 and increased IFN-γ in patients with asthma and in animal models, but its bioactive compound is unknown. Ganoderic acid beta (GAB) was isolated from Ganoderma lucidum (one herb in ASHMI). Human peripheral blood mononuclear cells (PBMCs) from adult patients with asthma were cultured with GAB or dexamethasone (Dex) in the presence of environmental allergens. The cytokine levels of IL-10, IFN-γ, IL-5, transcription factors T-bet, Foxp-3, and GATA3 were measured. Following 3-day culture, GAB, but not Dex, significantly increased IL-10 and IFN-γ levels by allergic patients' PBMCs. Following 6-day treatment, GAB inhibited IL-5 production, but IL-10 and IFN-γ remained high. Dex suppressed production of all three cytokines. GAB suppressed GATA3 and maintained Foxp-3 and T-bet gene expression, while Dex significantly suppressed GATA3 and T-bet expression. GAB simultaneously increased IL-10, IFN-γ associated with induction of T-bet and Foxp3, while suppressing IL-5, which was associated with suppression of GATA3, demonstrating unique beneficial cytokine modulatory effect, which distinguishes from Dex's overall suppression.

Ameliorative Effect of Imperatorin on Dermatophagoides pteronyssinus-Induced Allergic Asthma by Suppressing the Th2 Response in Mice.

Imperatorin is a furanocoumarin derivative and an effective ingredient in several Chinese medicinal herbs. It has favorable expectorant, analgesic, and anti-inflammatory effects. In this study, we investigated whether imperatorin has protective effects against Dermatophagoides pteronyssinus (Der p)-induced asthma in mice. Lung and bronchial tissues were histopathologically examined through hematoxylin-eosin staining. The concentrations of immunoglobin E (IgE), IgG1, IgG2a in serum and those of T helper 1 (Th1) and two cytokines and eosinophil-activated chemokines in bronchoalveolar lavage fluid (BALF) were detected using an enzyme immunoassay. Histological examination revealed that imperatorin reduced inflammatory cell infiltration, mucus hypersecretion, and endothelial cell hyperplasia. The examination also indicated that imperatorin could reduce the inflammatory cell count in BALF as well as IgE and IgG1 expression in serum, but IgG2a expression was significantly increased. Imperatorin reduced the production of interleukin (IL)-4, IL-5, and IL-13 by Th2, promoted the production of interferon-γ and IL-12 by Th1, and increased the production of IL-10 in bronchoalveolar lavage fluid. These findings suggest that imperatorin has a considerable anti-inflammatory effect on Der p-induced allergic asthma in mice.

Anti-interleukin-13 and anti-interleukin-4 agents versus placebo, anti-interleukin-5 or anti-immunoglobulin-E agents, for people with asthma.

BACKGROUND: Targeting the immunoglobulin E pathway and the interleukin-5 pathway with specific monoclonal antibodies directed against the cytokines or their receptors is effective in patients with severe asthma. However, there are patients who have suboptimal responses to these biologics. Since interleukin-4 and interleukin-13, signalling through the interleukin-4 receptor, have multiple effects on the biology of asthma, therapies targeting interleukin-4 and -13 (both individually and combined) have been developed. OBJECTIVES: To assess the efficacy and safety of anti-interleukin-13 or anti-interleukin-4 agents, compared with placebo, anti-immunoglobulin E agents, or anti-interleukin-5 agents, for the treatment of children, adolescents, or adults with asthma. SEARCH METHODS: We identified studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist for the Group and through searches of the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The search was carried out on the 16 October 2020. SELECTION CRITERIA: We included parallel-group randomised controlled trials that compared anti-interleukin-13 or -4 agents (or agents that target both interleukin-13 and interleukin-4) with placebo in adolescents and adults (aged 16 years or older) or children (younger than 16 years), with a diagnosis of asthma; participants could receive their usual short- or long-acting medications (e.g. inhaled corticosteroids (ICS), long-acting beta adrenoceptor agonists (LABA), long-acting muscarinic antagonists (LAMA), and/or leukotriene receptor antagonists) provided that they were not part of the randomised treatment. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. MAIN RESULTS: We identified and included 41 RCTs. Of these, 29 studies contributed data to the quantitative analyses, randomly assigning 10,604 people with asthma to receive an anti-interleukin-13 (intervention) or anti-interleukin-4 agent (intervention), or placebo (comparator). No relevant studies were identified where the comparator was an anti-immunoglobulin agent or an anti-interleukin-5 agent. Studies had a duration of between 2 and 52 (median 16) weeks. The mean age of participants across the included studies ranged from 22 to 55 years. Only five studies permitted enrolment of children and adolescents, accounting for less than 5% of the total participants contributing data to the present review. The majority of participants had moderate or severe uncontrolled asthma. Concomitant ICS use was permitted or required in the majority (21 of 29) of the included studies. The use of maintenance systemic corticosteroids was not permitted in 19 studies and was permitted or required in five studies (information not reported in five studies). Regarding the most commonly assessed anti-interleukin-13/-4 agents, four studies evaluated dupilumab (300 mg once every week (Q1W), 200 mg once every two weeks (Q2W), 300 mg Q2W, 200 mg once every four weeks (Q4W), 300 mg Q4W, each administered by subcutaneous (SC) injection); eight studies evaluated lebrikizumab (37.5 mg Q4W, 125 mg Q4W, 250 mg Q4W each administered by SC injection); and nine studies (3259 participants) evaluated tralokinumab (75 mg Q1W, 150 mg Q1W, 300 mg Q1W, 150 mg Q2W, 300 mg Q2W, 600 mg Q2W, 300 mg Q4W, each administered by SC injection; 1/5/10 mg/kg administered by intravenous (IV) injection); all anti-interleukin-13 or-4 agents were compared with placebo. The risk of bias was generally considered to be low or unclear (insufficient detail provided); nine studies were considered to be at high risk for attrition bias and three studies were considered to be at high risk for reporting bias. The following results relate to the primary outcomes. The rate of exacerbations requiring hospitalisation or emergency department (ED) visit was probably lower in participants receiving tralokinumab versus placebo (rate ratio 0.68, 95% CI 0.47 to 0.98; moderate-certainty evidence; data available for tralokinumab (anti-interleukin-13) only). In participants receiving an anti-interleukin-13/-4 agent, the mean improvement versus placebo in adjusted asthma quality of life questionnaire score was 0.18 units (95% CI 0.12 to 0.24; high-certainty evidence); however, this finding was deemed not to be a clinically relevant improvement. There was likely little or no difference between groups in the proportion of patients who reported all-cause serious adverse events (anti-interleukin-13/-4 agents versus placebo, OR 0.91, 95% CI 0.76 to 1.09; moderate-certainty evidence). In terms of secondary outcomes, there may be little or no difference between groups in the proportion of patients who experienced exacerbations requiring oral corticosteroids (anti-interleukin-13/-4 agents versus placebo, rate ratio 0.98, 95% CI 0.72 to 1.32; low-certainty evidence). Anti-interleukin-13/-4 agents probably improve asthma control based on asthma control questionnaire score (anti-interleukin-13/-4 agents versus placebo, mean difference -0.19; 95% CI -0.24 to -0.14); however, the magnitude of this result was deemed not to be a clinically relevant improvement. The proportion of patients experiencing any adverse event was greater in those receiving anti-interleukin-13/-4 agents compared with those receiving placebo (OR 1.16, 95% CI 1.04 to 1.30; high-certainty evidence); the most commonly reported adverse events in participants treated with anti-interleukin-13/-4 agents were upper respiratory tract infection, nasopharyngitis, headache and injection site reaction. The pooled results for the exploratory outcome, the rate of exacerbations requiring oral corticosteroids (OCS) or hospitalisation or emergency department visit, may be lower in participants receiving anti-interleukin-13/-4 agents versus placebo (rate ratio 0.71, 95% CI 0.65 to 0.77; low-certainty evidence). Results were generally consistent across subgroups for different classes of agent (anti-interleukin-13 or anti-interleukin-4), durations of study and severity of disease. Subgroup analysis based on category of T helper 2 (TH2) inflammation suggested greater efficacy in patients with higher levels of inflammatory biomarkers (blood eosinophils, exhaled nitric oxide and serum periostin). AUTHORS' CONCLUSIONS: Based on the totality of the evidence, compared with placebo, anti-interleukin-13/-4 agents are probably associated with a reduction in exacerbations requiring hospitalisation or ED visit, at the cost of increased adverse events, in patients with asthma. No clinically relevant improvements in health-related quality of life or asthma control were identified. Therefore, anti-interleukin-13 or anti-interleukin-4 agents may be appropriate for adults with moderate-to-severe uncontrolled asthma who have not responded to other treatments. These conclusions are generally supported by moderate or high-certainty evidence based on studies with an observation period of up to one year.

[Anti-IL-5 treatments in severe eosinophilic asthma: real life datas]. / Agir eozinofilik astimda anti-IL-5 tedaviler: gerçek yasam verileri.

Randomized controlled studies have shown that anti-IL-5 treatments reduce the need for oral corticosteroids, annual asthma exacerbation and hospitalization rates, blood eosinophil count and increase FEV1 values, asthma control, and quality of life in patients with eosinophilic severe asthma. Although the number of real-life studies with anti-IL-5 is limited, there are 10 real life studies with mepolizumab, one real life study with benralizumab and one real life study with reslizumab in the current literature. Similar to randomized controlled trials, real-life studies reported that a reduction in the need for oral corticosteroids, annual asthma exacerbation and hospitalization rates, and blood eosinophil counts and increase FEV1 values, asthma control test and quality of life scores, Response criteria were defined in some of the real-life studies and although different response rates were given according to these criteria, most of the patients with severe eosinophilic asthma showed high response rates to anti-IL-5 treatments. In real-life studies evaluating the safety of anti-IL-5 treatments, the most common adverse effect is mild local injection site reaction that does not require treatment, in conclusion, real-life studies suggest that all three anti-IL-5 treatments in clinical practice are effective and well tolerated.

[Efficacy and safety of anti-interleukin-5 therapy in patients with asthma: systematic reviews].

Objective: To evaluate the efficacy and safety of anti-Interleukin-5 therapy in patients with asthma. Methods: Data were collected from PubMed, E-Mbase, Springer, Ovid, Cochrane Library, ClinicalTrials.gov, CNKI and Wanfang database (-Feb 2017). Bibliographies of the retrieved articles were checked and analyzed. Results: Twenty publications involving a total of 6 406 patients were used in the analysis, including 23 randomly controlled trials (RCTs) which compared anti-interleukin 5 monoclonal antibody with placebo. Pooled analyses showed that anti-interleukin 5 monoclonal antibody significantly reduced exacerbation risk [RR=0.66, 95%CI(0.59, 0.73)], increased FEV(1)[MD=0.10, 95%CI(0.07, 0.13)] and FEV(1)% predicted [MD=3.90, 95%CI(1.86, 5.95)], and improved the scores on the Asthma Quality of Life Questionnaire (AQLQ) [MD=0.24, 95%CI(0.16, 0.32)]. Anti-interleukin 5 monoclonal antibody was also associated with significantly decreased risk of adverse events than placebo[OR=0.71, 95%CI(0.58, 0.87)]. Conclusion: Anti-interleukin 5 monoclonal antibody reduces the risk of exacerbations and improves quality of life in patients with asthma, and is tolerated well.

Eosinophilic Esophagitis: Impact of Latest Insights Into Pathophysiology on Therapeutic Strategies.

Eosinophilic esophagitis (EoE) has been defined as a 'chronic, immune/antigen-mediated, esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation'. A peak value of ≥15 eosinophils/high power field has been defined as histologic diagnostic cutoff. Other conditions associated with esophageal eosinophilia, such as gastro-esophageal reflux disease, PPI-responsive esophageal eosinophilia or Crohn's disease, need to be ruled out before EoE can be diagnosed. Males are affected more frequently than females and most of the patients have concomitant allergies. Currently, the EoE prevalence is about 1 of 2,000 inhabitants in Westernized countries. The first EoE patients were described only 2 decades ago. Despite this short period, considerable progress has been made regarding the understanding of the pathophysiology, natural history, assessment of disease activity and with respect to evaluating different therapeutic options. Untreated EoE can lead to esophageal remodeling with reduced compliance and stricture formation, which represents the main risk factor for food bolus impactions. The therapeutic options can be summarized with the 3 D's, which stand for drugs, diets and dilation. Of note, as of yet, there is no EoE-specific drug that has been approved by regulatory authorities. This is, among other reasons, related to the lack of validated outcome measurement instruments until recently. Swallowed topical steroids such as budesonide or fluticasone represent the standard of care for treating symptomatic pediatric and adult EoE patients with inflammatory activity. Several trials have already evaluated different biologic therapies, such as anti-interleukin-5 or anti-IgE. Further studies are on the way. As a non-pharmacologic alternative, different dietary regimens exist. Dilation can offer long-lasting symptomatic response in case of stricturing EoE but does not have any impact on the underlying inflammation. This review highlights the latest insights regarding pathophysiology and its impact regarding current and future therapeutic strategies.

[Predictive Value of Peripheral Blood Biomarkers in the Treatment of 
Lung Cancer Patients with Anti PD-1 Immunotherapy].

BACKGROUND: The application of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies has greatly improved the clinical outcomes of lung cancer patients. Here, we retrospectively analyzed the efficacy of PD-1 antibody therapy in locally advanced non-surgical or metastatic lung cancer patients, and preliminarily explored the correlation between peripheral blood biomarkers and clinical responses. METHODS: We conducted a single center study that included 61 IIIA-IV lung cancer patients who received PD-1 antibody treatment from March 2020 to December 2021, and collected the medical record data on PD-1 antibody first-line or second-line treatment. The levels of multiple Th1 and Th2 cytokines in the patient's peripheral blood serum, as well as the phenotype of peripheral blood T cells, were detected and analyzed. RESULTS: All the patients completed at least 2 cycles of PD-1 monoclonal antibody treatment. Among them, 42 patients (68.9%) achieved partial response (PR); 7 patients (11.5%) had stable disease (SD); and 12 patients (19.7%) had progressive disease (PD). The levels of peripheral blood interferon gamma (IFN-γ) (P=0.023), tumor necrosis factor α (TNF-α) (P=0.007) and interleukin 5 (IL-5) (P=0.002) before treatment were higher in patients of the disease control rate (DCR) (PR+SD) group than in the PD group. In addition, the decrease in absolute peripheral blood lymphocyte count after PD-1 antibody treatment was associated with disease progression (P=0.023). Moreover, the levels of IL-5 (P=0.0027) and IL-10 (P=0.0208) in the blood serum after immunotherapy were significantly increased compared to baseline. CONCLUSIONS: Peripheral blood serum IFN-γ, TNF-α and IL-5 in lung cancer patients have certain roles in predicting the clinical efficacy of anti-PD-1 therapy. The decrease in absolute peripheral blood lymphocyte count in lung cancer patients is related to disease progression, but large-scale prospective studies are needed to further elucidate the value of these biomarkers.

Wogonoside Ameliorates Airway Inflammation and Mucus Hypersecretion via NF-κB/STAT6 Signaling in Ovalbumin-Induced Murine Acute Asthma.

Asthma is recognized as a chronic respiratory illness characterized by airway inflammation and airway hyperresponsiveness. Wogonoside, a flavonoid glycoside, is reported to significantly alleviate the inflammation response and oxidative stress. Herein, this study aimed to investigate the therapeutic effect and underlying mechanism of wogonoside on airway inflammation and mucus hypersecretion in a murine asthma model and in human bronchial epithelial cells (16HBE). BALB/c mice were sensitized and challenged with ovalbumin (OVA). Pulmonary function and the number of cells in the bronchoalveolar lavage fluid (BALF) were examined. Pathological changes in lung tissue in each group were evaluated via hematoxylin and eosin and periodic acid-Schiff staining, and changes in levels of cytokines in BALF and of immunoglobulin E in serum were determined via an enzyme-linked immunosorbent assay. The expression of relevant genes in lung tissue was analyzed via real-time PCR. Western blotting and immunofluorescence were employed to detect the expression of relevant proteins in lung tissue and 16HBE cells. Treatment with 10 and 20 mg/kg wogonoside significantly attenuated the OVA-induced increase of inflammatory cell infiltration, mucus secretion, and goblet cell percentage and improved pulmonary function. Wogonoside treatment reduced the level of T-helper 2 cytokines including interleukin (IL)-4, IL-5, and IL-13 in BALF and of IgE in serum and decreased the mRNA levels of cytokines (IL-4, IL-5, IL-6, IL-13, and IL-1ß and tumor necrosis factor-α), chemokines (CCL-2, CCL-11, and CCL-24), and mucoproteins (MUC5AC, MUC5B, and GOB5) in lung tissues. The expression of MUC5AC and the phosphorylation of STAT6 and NF-κB p65 in lung tissues and 16HBE cells were significantly downregulated after wogonoside treatment. Thus, wogonoside treatment may effectively decrease airway inflammation, airway remodeling, and mucus hypersecretion via blocking NF-κB/STAT6 activation.

The consequences of not having eosinophils.

Several lines of evidence suggest that deficiency of eosinophils is not associated with any characteristic abnormality. Patients lacking eosinophils, in the setting of immunodeficiency or as a consequence of IgG-mediated eosinophil precursor destruction, do not display any distinguishing abnormalities related to eosinophil reduction. The observation that eosinophil-deficient mice do not display any distinctive syndrome or failure of their health is evidence that, under ordinary laboratory conditions, the eosinophil does not play a critical role in the well-being of mammals. Observations that monoclonal antibodies to interleukin-5 (IL-5) are well tolerated appear unsurprising in light of these findings. For example, patients with the hypereosinophilic syndrome have received mepolizumab, an anti-IL-5 monoclonal antibody, for as long as 6 years and have not developed any characteristic set of adverse events. Safety data for reslizumab, another anti-IL-5 monoclonal antibody, and benralizumab, a monoclonal antibody to the IL-5 receptor α-chain, are comparatively limited, especially for benralizumab, although reports of administration of these antibodies to humans suggest that they are well tolerated. Thus, data to the present suggest that reduction of eosinophils appears to have no characteristic ill effects on normal health, and monoclonal antibodies that deplete eosinophils have the potential to be widely employed in the treatment of eosinophil-associated diseases.

Pathogenic helper T cells as the novel therapeutic targets for immune-mediated intractable diseases.

Allergic diseases arise from a complex interplay between immune system and environmental factors. A link between the pathogenesis of allergic diseases and type 2 immune responses has become evident, with conventional and pathogenic type 2 helper T (Th2) cells involved in both. Recently, there has been a significant development in therapeutic agents for allergic diseases: IL-5 and IL-5 receptor antagonists, Janus kinase (JAK) inhibitors, and sublingual immunotherapy (SLIT). Mepolizumab, an IL-5, and Benralizumab, an IL-5 receptor antagonist, modulate eosinophilic inflammation mediated by IL-5-producing Th2 cells. Delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in atopic dermatitis, one of the common allergic diseases. SLIT has a significant effect on allergic rhinitis by reducing pathogenic Th2 cell numbers. More recently, novel molecules that are involved in pathogenic Th2 cell-mediated allergic diseases have been identified. These include calcitonin gene-related peptide (CGRP), reactive oxygen species (ROS) scavenging machinery regulated by the Txnip-Nrf2-Blvrb axis, and myosin light chain 9 (Myl9), which interacts with CD69. This review provides an updated view of the recent research on treatment of allergic diseases and their cause: conventional and pathogenic Th2 cells.

The effect of anti-IL5 monoclonal antibodies on regulatory and effector T cells in severe eosinophilic asthma.

INTRODUCTION: Biological treatments have redesigned the clinical management of severe eosinophilic asthmatic (SA) patients. Despite emerging evidence supporting the role of natural Killer (NK), and T regulatory cells (Treg) in the pathogenesis of asthma, no data is available on the effects of anti-IL5/IL5R therapies on these cell subsets. METHODS: We prospectively enrolled fourteen SA patients treated with benralizumab (n = 7) or mepolizumab (n = 7) and compared them with healthy controls (HC) (n = 11) and mild to moderate asthmatic (MM) patients (n = 9). Clinical parameters were collected at baseline (T0) and during follow-up. Cellular analysis, including the analysis of T/NK cell subsets, was determined through multicolor flow cytometry. RESULTS: At T0, SA patients showed higher percentages of CD4 TEM (33.3 ± 17.9 HC, 42.6 ± 16.6 MM and 66.1 ± 19.7 in SA; p < 0.0001) than HC and MM patients. With different timing, the two drugs induce a reduction of CD4 TEM ( 76 ± 19 T0; 43 ± 14 T1; 45 ± 23 T6; 62 ± 18 at T24; p < 0.0001 for mepolizumab and 55 ± 21 T0; 55 ± 22 T1; 43 ± 14 T6; 27 ± 12 at T24; p < 0.0001 for benralizumab) and an increase of Treg cells (1.2 ± 1.3 T0; 5.1 ± 2.5 T1; 6.3 ± 3.4 T6; 8.4 ± 4.6 at T24; p < 0.0001 for mepolizumab and 3.4 ± 1.7 T0; 1.9 ± 0.8 T1; 1.9 ± 1 T6; 5.1 ± 2.4 at T24; p < 0.0001 for benralizumab). The change of CD56dim PD-1+ significantly correlated with FEV1% (r = - 0.32; p < 0.01), while Treg expressing PD-1 correlates with the use of oral steroids ( r = 0.36 p = 0.0008) and ACT score (r = 0.36 p = 0.0008) p < 0.001) CONCLUSIONS: Beyond the clinical improvement, anti-IL-5 treatment induces a rebalancing of Treg and T effector cells in patients with SA.

Recent developments in the use of monoclonal antibodies targeting the type 2 cytokines for severe asthma treatment.

Severe or refractory asthma is seen in approximately 5% of asthmatic subjects who have unsatisfactory symptom control despite adherence to high-dose inhaled glucocorticoid therapies resulting in significant morbidity, reduced quality of life with attendant implications for healthcare costs. Marked heterogeneity in symptoms and at the molecular phenotypic level are hallmarks of asthma resulting in the requirement of specifically targeted treatments to block the key pathways of the disease. Monoclonal antibody (mAb)-based biologics targeted at inhibition of the type 2 cytokines IL-4, IL-5 and IL-13 have become established as effective treatments for severe asthma, with significant clinical benefit seen in carefully selected patient populations that take asthma phenotypes and endotypes into account. The further development of reproducible and straightforward discriminatory biomarkers may aid identification of those patients most likely to benefit from treatment with these interventions.

The effect of early radiofrequency turbinate reduction, intranasal steroid, and antihistamine H-1 on persistent allergic rhinitis: a randomized clinical trial.

OBJECTIVE: We aimed to evaluate the effect of radiofrequency turbinate reduction as an initial treatment on clinical improvement, inflammatory mediators, and remodeling process. METHODS: Between July 2018-February 2020, 32 patients with moderate-severe persistent AR were randomly divided into 2 groups. Intervention group received radiofrequency turbinate reduction followed by intranasal steroid and Antihistamine H-1 (AH-1), control group received intranasal steroid and AH-1. Both groups were evaluated for clinical improvement (using visual analogue scale based on total nasal symptoms score, peak nasal inspiratory flow, and turbinate size using imageJ) after 4 and 8 weeks of treatment. Inflammatory mediators (ELISA from nasal secretions was performed to measure ECP, IL-5, and HSP-70) and remodeling markers (nasal biopsy followed by immunohistochemistry examination was performed to evaluate MMP-9, TIMP-1, and PAI-1) were evaluated in week 4. RESULTS: Three patients dropped out of the study, resulting in 16 patients in intervention group and 13 patients in control group. At week 4, clinical response improved significantly in the intervention group compared to control group (Chi-Square test, p < 0.05). Compared to control, intervention group experienced a reduction of IL-5 and no significant change in ECP level (Mann Whitney test, p > 0.05). Reduction in the ratio of MMP-9/TIMP-1 were significantly higher in intervention group (unpaired t-test, p < 0,05). Meanwhile, increase in HSP-70 in the intervention group was slightly lower than in control group, but the difference with control group was not significant (Mann Whitney test, p > 0.05). CONCLUSION: Early radiofrequency turbinate reduction followed by pharmacotherapy given to persistent moderate-severe AR patients give more improvement only in early clinical symptoms and reduce MMP-9/TIMP-1 ratio, thus it might be suggested as one of the adjuvant therapies for the management of moderate-severe persistent AR. However, further investigation with a larger sample size and longer follow-up period is needed. LEVEL OF EVIDENCE: 1B.