Structure-activity relationship studies of pyrogallol as a calcineurin/NFAT signaling suppressor.

Previously, we have shown that pyrogallol alleviated nasal symptoms and suppressed IL-9 gene up-regulation in allergy model rats by inhibiting calcineurin/NFAT signaling. As pyrogallol has antioxidative activity, it may be responsible for inhibiting calcineurin/NFAT signaling-mediated IL-9 gene expression. However, the relationship between antioxidative activity and suppression of IL-9 gene expression has not been elucidated yet. Here, we conducted the structure-activity relationship studies of pyrogallol and its structurally related compounds to understand the mechanism of IL-9 gene suppression by pyrogallol. 2, 2-Diphenyl-1-picrylhydrazyl radical scavenging assay showed that the antioxidative activity of catechol, resorcinol, phloroglucinol, and gallic acid is 60.1%, 10.4%, 18.8%, and 113.5% of pyrogallol, respectively. Catechol, resorcinol, and phloroglucinol did not suppress NFAT dephosphorylation. Gallic acid suppressed dephosphorylation of NFAT. Gallic acid also suppressed ionomycin-induced up-regulation of IL-9 gene expression with the IC50 value of 82.6 µM. However, catechol, resorcinol and phloroglucinol showed no suppressive activity. In addition, using gallic acid-immobilized beads, we isolated and identified Poly(U)-binding-splicing factor 60 (PUF60) as a pyrogallol binding protein. These results suggest that the antioxidative activity of pyrogallol is not likely to be the mechanism of IL-9 gene suppression. Data also suggest that PUF60 is one of its target molecules responsible for the suppression of calcineurin/NFAT signaling by pyrogallol.

Infection-Induced SARS-CoV-2 Seroprevalence among Blood Donors, Japan, 2022.

A nationwide survey of SARS-CoV-2 antinucleocapsid seroprevalence among blood donors in Japan revealed that, as of November 2022, infection-induced seroprevalence of the population was 28.6% (95% CI 27.6%-29.6%). Seroprevalence studies might complement routine surveillance and ongoing monitoring efforts to provide a more complete real-time picture of COVID-19 burden.

Seroepidemiology and Carriage of Diphtheria in Epidemic-Prone Area and Implications for Vaccination Policy, Vietnam.

In 2019, a community-based, cross-sectional carriage survey and a seroprevalence survey of 1,216 persons 1-55 years of age were conducted in rural Vietnam to investigate the mechanism of diphtheria outbreaks. Seroprevalence was further compared with that of an urban area that had no cases reported for the past decade. Carriage prevalence was 1.4%. The highest prevalence, 4.5%, was observed for children 1-5 years of age. Twenty-seven asymptomatic Coerynebacterium diphtheriae carriers were identified; 9 carriers had tox gene-bearing strains, and 3 had nontoxigenic tox gene-bearing strains. Child malnutrition was associated with low levels of diphtheria toxoid IgG, which might have subsequently increased child carriage prevalence. Different immunity patterns in the 2 populations suggested that the low immunity among children caused by low vaccination coverage increased transmission, resulting in symptomatic infections at school-going age, when vaccine-induced immunity waned most. A school-entry booster dose and improved infant vaccination coverage are recommended to control transmissions.

Association of pneumococcal carriage in infants with the risk of carriage among their contacts in Nha Trang, Vietnam: A nested cross-sectional survey.

BACKGROUND: Infants are at highest risk of pneumococcal disease. Their added protection through herd effects is a key part in the considerations on optimal pneumococcal vaccination strategies. Yet, little is currently known about the main transmission pathways to this vulnerable age group. Hence, this study investigates pneumococcal transmission routes to infants in the coastal city of Nha Trang, Vietnam. METHODS AND FINDINGS: In October 2018, we conducted a nested cross-sectional contact and pneumococcal carriage survey in randomly selected 4- to 11-month-old infants across all 27 communes of Nha Trang. Bayesian logistic regression models were used to estimate age specific carriage prevalence in the population, a proxy for the probability that a contact of a given age could lead to pneumococcal exposure for the infant. We used another Bayesian logistic regression model to estimate the correlation between infant carriage and the probability that at least one of their reported contacts carried pneumococci, controlling for age and locality. In total, 1,583 infants between 4 and 13 months old participated, with 7,428 contacts reported. Few infants (5%, or 86 infants) attended day care, and carriage prevalence was 22% (353 infants). Most infants (61%, or 966 infants) had less than a 25% probability to have had close contact with a pneumococcal carrier on the surveyed day. Pneumococcal infection risk and contact behaviour were highly correlated: If adjusted for age and locality, the odds of an infant's carriage increased by 22% (95% confidence interval (CI): 15 to 29) per 10 percentage points increase in the probability to have had close contact with at least 1 pneumococcal carrier. Moreover, 2- to 6-year-old children contributed 51% (95% CI: 39 to 63) to the total direct pneumococcal exposure risks to infants in this setting. The main limitation of this study is that exposure risk was assessed indirectly by the age-dependent propensity for carriage of a contact and not by assessing carriage of such contacts directly. CONCLUSIONS: In this study, we observed that cross-sectional contact and infection studies could help identify pneumococcal transmission routes and that preschool-age children may be the largest reservoir for pneumococcal transmission to infants in Nha Trang, Vietnam.

Diagnostic Value of Advanced Metal Artifact Reduction Magnetic Resonance Imaging for Periprosthetic Joint Infection.

MATERIALS AND METHODS: Magnetic resonance imaging around metal joint prostheses including multiacquisition variable-resonance image combination selective at 1.5 T (from April 2014 to August 2020) was retrospectively evaluated by 2 radiologists for detection of abnormal findings (joint effusion, capsular thickening, pericapsular edema, soft-tissue fluid collection, soft-tissue edema, bone marrow edema pattern around the implant [BME pattern], lymphadenopathy, and others) and overall image impression for PJI. Regarding the soft-tissue fluid collection, presence of communication to the joint or capsular-like structure was evaluated. Clinical assessments were recorded. Positive predictive values (PPVs), negative predictive values (NPVs), and odds ratios (ORs) for PJI were calculated for the abnormal findings. Overall image impression for PJI was evaluated. χ2, Fisher exact, t, and Mann-Whitney U tests and receiver operating characteristic analysis were used. Interobserver agreement was assessed with κ statistics. RESULTS: Forty-three joints in 36 patients (mean ± SD age, 75.4 ± 8.8 years; 30 women; hip [n = 29], knee [n = 12], and elbow [n = 2]) were evaluated. Eighteen joints (42%) were clinically diagnosed as PJI. The findings suggesting PJI were capsular thickening (PPV, 70%; NPV, 90%; OR, 20.6), soft-tissue fluid collection (PPV, 81%; NPV, 81%; OR, 19.1), soft-tissue edema (PPV, 67%; NPV, 89%; OR, 17), pericapsular edema (PPV, 76%; NPV, 81%; OR, 13.7), and joint effusion (PPV, 55%; NPV, 100%; OR, 12). Soft-tissue fluid collection without capsular-like structure (PPV, 83%; NPV, 74%; OR, 14.4) or with communication to the joint (PPV, 75%; NPV, 71%; OR, 7.3) suggested PJI. The combinations of joint effusion, capsular thickening, pericapsular edema, soft-tissue fluid collection, and soft-tissue edema highly suggested PJI. Regarding the BME pattern, the combination with soft-tissue edema raised the possibility of PJI (PPV, 73%; NPV, 69%; OR, 5.9). Regarding the interobserver agreements for each abnormal finding, κ values were 0.60 to 0.77. Regarding the overall image impression, weighted κ value was 0.97 and areas under the receiver operating characteristic curve were 0.949 (95% confidence interval, 0.893-1.005) and 0.926 (95% confidence interval, 0.860-0.991) with no significant difference (P = 0.534). CONCLUSIONS: The findings suggesting PJI were capsular thickening, soft-tissue fluid collection, soft-tissue edema, pericapsular edema, and joint effusion. The combinations of them highly suggested PJI. Regarding the BME pattern, the combination with soft-tissue edema raised the possibility of PJI.

Public health and social measures to mitigate the health and economic impact of the COVID-19 pandemic in Turkey, Egypt, Ukraine, Kazakhstan, and Poland during 2020-2021: situational analysis.

BACKGROUND: The COVID-19 pandemic had a colossal impact on human society globally. There were similarities and differences in the public health and social measures taken by countries, and comparative analysis facilitates cross-country learning of contextual practices and sharing lessons to mitigate the COVID-19 pandemic impact. Our aim is to conduct a situational analysis of the public health and social measures to mitigate the health and economic impact of the COVID-19 pandemic in Turkey, Egypt, Ukraine, Kazakhstan, and Poland during 2020-2021. METHODS: We conducted a situational analysis of the COVID-19 pandemic response in Turkey, Egypt, Ukraine, Kazakhstan, and Poland from the perspectives of the health system and health finance, national coordination, surveillance, testing capacity, health infrastructure, healthcare workforce, medical supply, physical distancing and non-pharmaceutical interventions, health communication, impact on non-COVID-19 health services, impact on the economy, education, gender and civil liberties, and COVID-19 vaccination. RESULTS: Since the onset of the COVID-19 pandemic, Turkey, Egypt, Ukraine, Kazakhstan, and Poland have expanded COVID-19 testing and treatment capacity over time. However, they faced a shortage of healthcare workforce and medical supplies. They took population-based quarantine measures rather than individual-based isolation measures, which significantly burdened their economies and disrupted education. The unemployment rate increased, and economic growth stagnated. Economic stimulus policy was accompanied by high inflation. Despite the effort to sustain essential health services, healthcare access declined. Schools were closed for 5-11 months. Gender inequality was aggravated in Turkey and Ukraine, and an issue was raised for balancing public health measures and civil liberties in Egypt and Poland. Digital technologies played an important role in maintaining routine healthcare, education, and public health communication. CONCLUSIONS: The COVID-19 pandemic has exposed weaknesses in healthcare systems in the emerging economies of Turkey, Egypt, Ukraine, Kazakhstan, and Poland, and highlighted the intricate link between health and economy. Individual-level testing, isolation, and contact tracing are effective public health interventions in mitigating the health and economic impact of the COVID-19 pandemic in comparison to population-level measures of lockdowns. Smart investments in public health, including digital health and linking health security with sustainable development, are key for economic gain, social stability, and more equitable and sustainable development.

Identification of novel interacting regions involving calcineurin and nuclear factor of activated T cells.

Nuclear factor of activated T cells (NFAT) leads to the transcription of diverse inducible genes involved in many biological processes; therefore, aberrant NFAT expression is responsible for the development and exacerbation of various disorders. Since five isoforms of NFAT (NFATc1-c4, NFAT5) exhibit distinct and overlapping functions, selective control of a part, but not all, of NFAT family members is desirable. By comparing the binding activity of each NFATc1-c4 with its regulatory enzyme, calcineurin (CN), using a quantitative immunoprecipitation assay, we found a new CN-binding region (CNBR) selectively functioning in NFATc1 and NFATc4. This region, termed CNBR3, is located between two preexisting CNBR1 and CNBR2, within the Ca2+ regulatory domain. The nuclear translocation of NFATc1 but not NFATc2 in T cells was suppressed by ectopic expression of CNBR3 and, accordingly, NFATc1-dependent cytokine expression was downregulated. Through competition assays using NFATc1-derived partial peptides and mass spectrometry with photoaffinity technology, we identified 18 amino acids in NFATc1 (Arg258 to Pro275 ) and 13 amino acids in CN catalytic subunit (CNA) (Asn77 to Gly89 ) responsible for CNA/CNBR3 binding in which Cys263 and Asp82 , respectively, played crucial roles. The possible selective regulation of NFAT-mediated biological processes by targeting this new CN/NFAT-binding region is suggested.

Preoperative CT Findings for Predicting Acute Exacerbation of Interstitial Pneumonia After Lung Cancer Surgery: A Multicenter Case-Control Study.

BACKGROUND. Acute exacerbation (AE) is a life-threatening complication of inter-stitial pneumonia (IP). Thoracic surgery may trigger AE. OBJECTIVE. The purpose of this study is to explore the role of preoperative CT findings in predicting postoperative AE in patients with IP and lung cancer. METHODS. This retrospective case-control study included patients from 22 institutions who had IP and underwent thoracic surgery for lung cancer. AE was diagnosed on the basis of symptoms and imaging findings noted within 30 days after surgery and the absence of alternate causes. For each patient with AE, two control patients without AE were identified. After exclusions, the study included 92 patients (78 men and 14 women; 31 with AE [the AE group] and 61 without AE [the no-AE group]; mean age, 72 years). Two radiologists independently reviewed preoperative thin-slice CT examinations for pulmonary findings and resolved differences by consensus. The AE and no-AE groups were compared using the Fisher exact and Mann-Whitney U tests. Multivariable logistic regression was performed. Interreader agreement was assessed by kappa coefficients. RESULTS. A total of 94% of patients in the AE group underwent segmentectomy or other surgery that was more extensive than wedge resection versus 75% in the no-AE group (p = .046). The usual IP pattern was present in 58% of the AE group versus 74% of the no-AE group (p = .16). According to subjective visual scoring, the mean (± SD) ground-glass opacity (GGO) extent was 6.3 ± 5.4 in the AE group versus 3.9 ± 3.8 in the no-AE group (p = .03), and the mean consolidation extent was 0.5 ± 1.2 in the AE group versus 0.1 ± 0.3 in the no-AE group (p = .009). Mean pulmonary trunk diameter was 28 ± 4 mm in the AE group versus 26 ± 3 mm in the no-AE group (p = .02). In a model of CT features only, independent predictors of AE (p < .05) were GGO extent (odds ratio [OR], 2.8), consolidation extent (OR, 9.4), and pulmonary trunk diameter (OR, 4.2); this model achieved an AUC of 0.75, a PPV of 71%, and an NPV of 77% for AE. When CT and clinical variables were combined, undergoing segmentectomy or more extensive surgery also independently predicted AE (OR, 8.2; p = .02). CONCLUSION. The presence of GGO, consolidation, and pulmonary trunk enlargement on preoperative CT predicts AE in patients with IP who are undergoing lung cancer surgery. CLINICAL IMPACT. Patients with IP and lung cancer should be carefully managed when predictive CT features are present. Wedge resection, if possible, may help reduce the risk of AE in these patients. TRIAL REGISTRATION. University Hospital Medical Information Clinical Trial Registry UMIN000029661.

Isoform-Selective NFAT Inhibitor: Potential Usefulness and Development.

Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological events. Therefore, functional and/or structural abnormalities of NFAT are linked to the pathogenesis of diseases in various organs. The NFAT protein family consists of five isoforms, and each isoform performs diverse functions and has unique expression patterns in the target tissues. This diversity has made it difficult to obtain ideal pharmacological output for immunosuppressants that inhibit the activity of almost all NFAT family members, causing serious and wide-ranging side effects. Moreover, it remains unclear whether isoform-selective NFAT regulation can be achieved by targeting the structural differences among NFAT isoforms and whether this strategy can lead to the development of better drugs than the existing ones. This review summarizes the role of the NFAT family members in biological events, including the development of various diseases, as well as the usefulness of and problems associated with NFAT-targeting therapies, including those dependent on current immunosuppressants. Finally, we propose a novel therapeutic strategy based on the molecular mechanisms that enable selective regulation of specific NFAT isoforms.

Diphtheria Outbreaks in Schools in Central Highland Districts, Vietnam, 2015-2018.

During 2015-2018, seven schools in rural Vietnam experienced diphtheria outbreaks. Multilocus sequence types were the same within schools but differed between schools. Low vaccine coverage and crowded dormitories might have contributed to the outbreaks. Authorities should consider administering routine vaccinations and booster doses for students entering the school system.

A serological framework to investigate acute primary and post-primary dengue cases reporting across the Philippines.

BACKGROUND: In dengue-endemic countries, targeting limited control interventions to populations at risk of severe disease could enable increased efficiency. Individuals who have had their first (primary) dengue infection are at risk of developing more severe secondary disease, thus could be targeted for disease prevention. Currently, there is no reliable algorithm for determining primary and post-primary (infection with more than one flavivirus) status from a single serum sample. In this study, we developed and validated an immune status algorithm using single acute serum samples from reporting patients and investigated dengue immuno-epidemiological patterns across the Philippines. METHODS: During 2015/2016, a cross-sectional sample of 10,137 dengue case reports provided serum for molecular (anti-DENV PCR) and serological (anti-DENV IgM/G capture ELISA) assay. Using mixture modelling, we re-assessed IgM/G seroprevalence and estimated functional, disease day-specific, IgG:IgM ratios that categorised the reporting population as negative, historical, primary and post-primary for dengue. We validated our algorithm against WHO gold standard criteria and investigated cross-reactivity with Zika by assaying a random subset for anti-ZIKV IgM and IgG. Lastly, using our algorithm, we explored immuno-epidemiological patterns of dengue across the Philippines. RESULTS: Our modelled IgM and IgG seroprevalence thresholds were lower than kit-provided thresholds. Individuals anti-DENV PCR+ or IgM+ were classified as active dengue infections (83.1%, 6998/8425). IgG- and IgG+ active dengue infections on disease days 1 and 2 were categorised as primary and post-primary, respectively, while those on disease days 3 to 5 with IgG:IgM ratios below and above 0.45 were classified as primary and post-primary, respectively. A significant proportion of post-primary dengue infections had elevated anti-ZIKV IgG inferring previous Zika exposure. Our algorithm achieved 90.5% serological agreement with WHO standard practice. Post-primary dengue infections were more likely to be older and present with severe symptoms. Finally, we identified a spatio-temporal cluster of primary dengue case reporting in northern Luzon during 2016. CONCLUSIONS: Our dengue immune status algorithm can equip surveillance operations with the means to target dengue control efforts. The algorithm accurately identified primary dengue infections who are at risk of future severe disease.

Downregulation of NFAT3 Due to Lack of T-Box Transcription Factor TBX5 Is Crucial for Cytokine Expression in T Cells.

The NFAT family transcription factors play crucial roles in immunological and other biological activities. NFAT3 is rarely expressed in T cells, and the mechanisms and significance of the specific NFAT3 downregulation in T cells have been unknown. In human CD4+ T cells, overexpression of NFAT1 and NFAT3 enhanced and suppressed IL-2 expression, respectively. NFAT3 downregulation in Jurkat cells using RNA interference technology augmented IL-2 expression, whereas a knockdown of NFAT1, NFAT2, and NFAT4 suppressed it. The promoter/enhancer activity of the NFAT-binding site in the IL-2 gene was upregulated and downregulated by NFAT1 and NFAT3, respectively. A study employing NFAT1/NFAT3 chimeric molecules revealed that the region in NFAT3 responsible for NFAT promoter activity inhibition was located within its N-terminal transactivation domain, Ca2+-regulatory domain, and DNA-binding domain. Downregulation of NFAT3 expression in T cells is mediated by lower chromatin accessibility and enhancer activity in its promoter in comparison with aortic smooth muscle cells expressing endogenous NFAT3. The binding sites of T-box transcription factor TBX5 and NK-2 transcription factor-related locus 5 Nkx2.5, which were expressed at higher levels in aortic smooth muscle cells than in T cells, were located within the -387 to +97 NFAT3 promoter region, exhibiting the maximum enhancer activity. Mutating the binding site of TBX5 but not Nkx2.5 diminished the NFAT3 promoter activity, whereas the overexpression of TBX5 enhanced it. Introduction of TBX5 into CD4+ T cells enhanced the expression of NFAT3 and suppressed that of IL-2. TBX5 deficiency-mediated downregulation of NFAT3 is crucial for the high cytokine-producing activity of T cells.

Prevalence of non-communicable diseases and its risk factors among Ijegun-Isheri Osun residents in Lagos State, Nigeria: a community based cross-sectional study.

BACKGROUND: The rapid epidemiologic transition of diseases has adverse implications for low-and middle-income countries (LMICs) like Nigeria due to their limited healthcare, weaker health systems and the westernization of lifestyle. There is a need to evaluate the enormity or otherwise of non-communicable diseases (NCDs) burden in such low resource settings. We performed this survey to determine the prevalence of NCDs and its risk factors among the Ijegun- Isheri Osun community residents of Lagos, Nigeria. METHODS: A community-based cross-sectional survey was performed on 215 respondents recruited consecutively during a population preventive health campaign. Prevalence of three NCDs (hypertension, diabetes and dyslipidaemia) were calculated. Associations between each of these NCDs and selected risk factors were determined using chi square test. Multivariable logistic regression was used to estimate the risk factors of each of the three NCDs. RESULTS: The prevalence of hypertension was 35.3% (95% CI 29.0-42.1), diabetes 4.6% (95% CI 2.2-8.4) and dyslipidaemia 47.1% (95% CI 41.1-54.8). Among the NCD risk factors, the prevalence of smoking was 41.3% (95% CI 34.2-48.6), alcohol consumption 72.5% (95% CI 65.5-78.7), and physical activity 52.9 (95% CI 45.5-60.2). The independent significant predictors of hypertension were age ≥ 60 years (aOR 4.56; 95% CI: 1.72-12.09) and dyslipidaemia (aOR 5.01; 95% CI: 2.26-11.13). Age ≥ 60 years (aOR 8.83; 95% CI: 1.88-41.55) was an independent predictor of diabetes. Age ≥ 60 years (aOR 29.32; 95% CI: 4.78-179.84), being employed (aOR 11.12; 95% CI: 3.10-39.92), smoking (aOR 2.34; 95% CI: 1.03-5.33) and physical activity (aOR 0.34; 95% CI: 0.15-0.76) were independent predictors of having dyslipidaemia. CONCLUSIONS: The prevalence of hypertension, diabetes and dyslipidaemia and their associated risk factors are high among the respondents of Ijegun-Isheri Osun community of Lagos state, Nigeria. This highlights the need for further implementation research and policy directions to tackle NCD burden in urban communities in Nigeria. These strategies must be community specific, prioritizing the various risk factors and addressing them accordingly.

Contribution of neuraminidase 3 to the differentiation of induced regulatory T cells.

Neuraminidase family enzymes that hydrolyze the terminal sialic acid linkage in biomolecules are involved in various immune responses. We previously showed that Th1 and Th2 cells differentially express several neuraminidases. Herein, the expression of neuraminidases in induced regulatory T (iTreg) cells was investigated in comparison with that in other T-cell subsets. Contrary to the tendency toward higher neuraminidase 1 mRNA expression in in vitro-differentiated Th2 cells, compared to Th1, Th17 and iTreg cells, we observed significantly higher expression of neuraminidase 3 (Neu3) in iTreg cells. Furthermore, the expression of Neu3 in FoxP3+ CD62L- spleen cells was higher than that in FoxP3+ CD62L+ and FoxP3- cells. Lentiviral expression of Neu3 in naïve CD4+ T cells during the stimulation culture led to upregulation of FoxP3 expression. On the basis of these findings, we conclude that Neu3 contributes to the differentiation of iTreg cells by upregulation of FoxP3.

Hyper-reactive cloned mice generated by direct nuclear transfer of antigen-specific CD4+ T cells.

T-cell receptor (TCR)-transgenic mice have been employed for evaluating antigen-response mechanisms, but their non-endogenous TCR might induce immune response differently than the physiologically expressed TCR Nuclear transfer cloning produces animals that retain the donor genotype in all tissues including germline and immune systems. Taking advantage of this feature, we generated cloned mice that carry endogenously rearranged TCR genes from antigen-specific CD4+ T cells. We show that T cells of the cloned mice display distinct developmental pattern and antigen reactivity because of their endogenously pre-rearranged TCRα (rTα) and TCRß (rTß) alleles. These alleles were transmitted to the offspring, allowing us to establish a set of mouse lines that show chronic-type allergic phenotypes, that is, bronchial and nasal inflammation, upon local administrations of the corresponding antigens. Intriguingly, the existence of either rTα or rTß is sufficient to induce in vivo hypersensitivity. These cloned mice expressing intrinsic promoter-regulated antigen-specific TCR are a unique animal model with allergic predisposition for investigating CD4+ T-cell-mediated pathogenesis and cellular commitment in immune diseases.

Potential Mechanisms of T Cell-Mediated and Eosinophil-Independent Bronchial Hyperresponsiveness.

Bronchial asthma is a chronic disease characterized by reversible airway obstruction, mucus production, and bronchial hyperresponsiveness (BHR). Although Th2 cell-mediated eosinophilic inflammation is an important disease mechanism in the majority of patients with bronchial asthma, recent studies suggest the possible development of Th2-independent airway inflammation and BHR. These non-Th2 endotype patients seem to consist of multiple subgroups, and often do not respond to inhaled corticosteroids. Therefore, to understand the pathogenesis of asthma, it is important to characterize these non-Th2 subgroups. Recently, we demonstrated that Th9 cells induce eosinophil infiltration and eosinophil-independent BHR, and Th9 cells-mediated BHR may be resistant to glucocorticoid. In this review, we summarize the contribution of several T cell subsets in the development of bronchial asthma and introduce our recent study demonstrating Th9 cell-mediated and eosinophil-independent BHR.

Identification of biomarker sets for predicting the efficacy of sublingual immunotherapy against pollen-induced allergic rhinitis.

Sublingual immunotherapy (SLIT) is effective against allergic rhinitis, although a substantial proportion of individuals is refractory. Herein, we describe a predictive modality to reliably identify SLIT non-responders (NRs). We conducted a 2-year clinical study in 193 adult patients with Japanese cedar pollinosis, with biweekly administration of 2000 Japanese allergy units of cedar pollen extract as the maintenance dose. After identifying high-responder (HR) patients with improved severity scores and NR patients with unchanged or exacerbated symptoms, differences in 33 HR and 34 NR patients were evaluated in terms of peripheral blood cellular profiles by flow cytometry and serum factors by ELISA and cytokine bead array, both pre- and post-SLIT. Improved clinical responses were seen in 72% of the treated patients. Pre-therapy IL-12p70 and post-therapy IgG1 serum levels were significantly different between HR and NR patients, although these parameters alone failed to distinguish NR from HR patients. However, the analysis of serum parameters in the pre-therapy samples with the Adaptive Boosting (AdaBoost) algorithm distinguished NR patients with high probability within the training data set. Cluster analysis revealed a positive correlation between serum Th1/Th2 cytokines and other cytokines/chemokines in HR patients after SLIT. Thus, processing of pre-therapy serum parameters with AdaBoost and cluster analysis can be reliably used to develop a prediction method for HR/NR patients.

Effects of anti-allergic drugs on T cell-mediated nasal hyperresponsiveness in a murine model of allergic rhinitis.

BACKGROUND: We have recently demonstrated that T cell-mediated nasal hyperresponsiveness (NHR) is a representative pathophysiological feature of allergic rhinitis (AR). Although several anti-allergic drugs are used for the treatment of AR, the efficacy of these drugs on T cell-mediated NHR have not been elucidated. In these studies we investigated the effects of dexamethasone (Dex), montelukast (Mk), and chlorpheniramine (Chl) on NHR in antigen-immunized and antigen-specific Th2 cell-transferred mice. METHODS: OVA-immunized BALB/c mice were treated with Dex, Mk, or Chl and challenged intranasally with OVA. We then assessed NHR, the number of inflammatory cells in the nasal lavage fluid (NALF), mRNA expression of Th2 cytokines in the nasal tissue, the population of CD3+CD4+ cells in the nasal lymphoid tissue (NALT), and antigen-specific serum IgE and IgG levels. Antigen-induced NHR and changes in antigen-specific T cells in the NALT were investigated in OVA-specific Th2 cell-transferred mice. RESULTS: Dex significantly suppressed antigen-induced NHR, inflammatory cell infiltration, and IL-4, IL-5, IL-6, and IL-13 expression in immunized mice. Chl was completely ineffective, and only IL-13 expression was suppressed by Mk. None of these drugs affected IgE and IgG production. Antigen-induced NHR and the increase in antigen-specific T cells in the NALT of Th2 cell-transferred mice were inhibited by Dex, but not by Mk or Chl. CONCLUSIONS: Steroids are effective for the reduction of NHR in AR by suppressing the accumulation of inflammatory cells, especially antigen-specific T cells.

Differential Contribution of Adhesion Molecules to Th1 and Th2 Cell-Mediated Lung and Bowel Inflammation.

CD4+ T cells play a critical role in the development of allergic inflammation in several target organs. Various adhesion molecules are involved in the local recruitment of T cells and other inflammatory cells. We investigated the differential contribution of adhesion molecules to T helper 1 (Th1) and Th2 cell-mediated allergic lung and bowel inflammation by employing their neutralizing antibodies. BALB/c mice transferred with in vitro-differentiated antigen-specific Th1 and Th2 cells were intratracheally or intrarectally challenged with a relevant antigen. Infiltration of infused T cells occurred, along with the accumulation of neutrophils and eosinophils in the lungs of Th1 and Th2 cell-transferred recipients, respectively. Th1-mediated neutrophil and Th2-mediated eosinophil accumulation in the large intestine, which occurred after intrarectal challenge with the antigen, was indicated by the significant elevation of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activity. Blocking experiments with neutralizing antibodies indicated that intercellular cell adhesion molecule (ICAM)-1; vascular cell adhesion molecule (VCAM)-1; and αL, ß2, and ß7 integrins participate in the accumulation of Th2 cells and eosinophils in the lungs. In contrast, the migration of Th1 cells and neutrophils was diminished by blockage of αL/ß2-integrin and ICAM-1, respectively. Mucosal addressin cell adhesion molecule (MadCAM)-1, vascular cell adhesion molecule (VCAM)-1, α4, ß1, and ß7 contributed to Th1-mediated neutrophilic inflammation in the bowel, though only MadCAM-1, α4, αL, and ß2 were involved in Th2-mediated eosinophilic inflammation. We conclude that distinct sets of adhesion molecules are involved in Th1- and Th2-mediated allergic lung and bowel inflammation.

Oral administration of ovalbumin after sensitization attenuates symptoms in a mouse model of food allergic enteropathy.

Oral immunotherapy (OIT) is a promising treatment of food allergy. To administer an appropriate oral dose of an allergenic component as OIT to individuals sensitized with a food allergen may prevent inducing food allergic inflammation in them. So we attempted to establish a mouse model to evaluate efficacy for oral administration of food allergen after sensitization. In BALB/c mice sensitized by injecting ovalbumin (OVA) with alum twice, OVA was administered before inducing inflammation by feeding the mice with egg white (EW) diet. Severe inflammatory responses, such as enteropathy, weight loss, IL-4 production, and increase of IgE antibody levels, were suppressed by administration with 4 mg of OVA 7 times before feeding EW diet. OVA administration alone induced a slight Th2 response, but no symptoms. The current study demonstrated that severe food allergic enteropathy could be prevented by pre-administration with appropriate dose of OVA to sensitized mice.