Publications by authors named "Yi-Giien Tsai"

33 Publications

Heat Shock Protein-70 Levels Are Associated With a State of Oxidative Damage in the Development of Bronchopulmonary Dysplasia.

Front Pediatr 2021 26;9:616452. Epub 2021 May 26.

Department of Pediatrics, Changhua Christian Children's Hospital, Changhua, Taiwan.

Heat shock protein-70 (Hsp-70) exhibits cytoprotective effects against oxidative stress-induced airway injury. This study aimed to examine Hsp-70 and 8-hydroxy-2'-deoxyguanosine (8-OHdG) from tracheal aspirates (TA) in very low-birth weight (VLBW) preterm infants to predict the development of bronchopulmonary dysplasia (BPD). This birth cohort study enrolled 109 VLBW preterm infants, including 32 infants who developed BPD. Hsp-70 and 8-OHdG concentrations from TA were measured by immunoassay. The apoptosis of TA epithelial cells obtained on Day 28 after birth was measured using annexin-V staining assay. Hsp-70 and 8-OHdG levels in TA fluid were persistently increased from Day 1 to Day 28 of life in the BPD group. Multiple linear regression analysis demonstrated that BPD was significantly associated with gestational age, respiratory distress syndrome, and TA Hsp-70 and 8-OHdG levels on post-natal Day 28. The TA Hsp-70 level positively correlated with TA 8-OHdG level on the Day 1 ( = 0.47) and Day 28 of life ( = 0.68). Incubation of recombinant Hsp-70 with primary epithelial cells derived from TA of patients decreased hydrogen peroxide-induced epithelial cell death. Hsp-70 levels are associated with a state of oxidative injury in the development of BPD.
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http://dx.doi.org/10.3389/fped.2021.616452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187579PMC
May 2021

Acrylamide Induces Mitophagy and Alters Macrophage Phenotype via Reactive Oxygen Species Generation.

Int J Mol Sci 2021 Feb 8;22(4). Epub 2021 Feb 8.

Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Acrylamide is a readily exposed toxic organic compound due to its formation in many carbohydrate rich foods that are cooked at high temperatures. Excessive production of reactive oxygen species (ROS), which is an important factor for mitophagy, has been reported to lead to airway inflammation, hyper-responsiveness, and remodeling. Epigenetic regulation is an important modification affecting gene transcription. In this study, the effects of acrylamide on ROS productions and mitophagy were investigated. The human monocytic cell line THP-1 was treated with acrylamide, and ROS productions were investigated by flow cytometry. The mitochondrial and epigenetic involvement was evaluated by quantitative real-time PCR. Histone modifications were examined by chromatin immunoprecipitation assays. Mitophagy was detected by Western blotting and confocal laser microscopy. Acrylamide promoted mitochondria-specific ROS generation in macrophages. The gene expression of mitochondrial respiratory chain complex II was increased under acrylamide treatment. Acrylamide induced histone H3K4 and H3K36 tri-methylation in an promoter and increased mitophagy-related PINK1 expression, which promoted a M2-like phenotypic switch with increase TGF-β and CCL2 levels in THP-1 cells. In conclusion, acrylamide induced ROS production through histone tri-methylation in an promoter and further increased the expression of mitophagy-related PINK-1, which was associated with a macrophage M2 polarization shift.
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http://dx.doi.org/10.3390/ijms22041683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914752PMC
February 2021

Diagnostic procedures & practices in drug allergy/hypersensitivity: a survey of 13 Asian countries.

Asia Pac Allergy 2020 Oct 15;10(4):e36. Epub 2020 Oct 15.

Department of Pediatrics, Nippon Medical School, Tokyo, Japan.

Background: The issues and challenges in the diagnosis of drug allergy/hypersensitivity among children and adults in Asia are likely to be different from non-Asian countries.

Objective: To study the diagnostic modalities used in the evaluation and management of drug allergy/drug hypersensitivity reactions (DHRs) among member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI).

Methods: A questionnaire comprising 41 questions was circulated electronically to member societies and individual members of APAAACI between January 23, 2020 and March 6, 2020.

Results: Twenty-six respondents from 15 member societies and 1 individual member responded. European DHR guidelines were most commonly used. Skin prick and intradermal testing was used by 100%, with only 60% having access to commercial penicillin skin test reagents. -specific IgE tests were used by 75%, and basophil activation test by 56.3% for immediate DHR. Patch tests were used by 75% in contrast to lymphocyte transformation tests by 25% for nonimmediate DHR. Drug provocation tests were used by 68.8%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (93.3%). Human leukocyte antigen (HLA) genotype testing was mandatory among 25% respondents before new carbamazepine prescriptions, and 8.3% for allopurinol prescriptions.

Conclusions: There was increased use of skin testing for iodinated contrast media hypersensitivity and patch testing for nonimmediate DHR. HLA genotype testing prior to new carbamazepine, allopurinol and abacavir prescriptions remain variable despite strong associations for severe cutaneous adverse reactions with Asian ethnicity. Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across APAAACI member societies.
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http://dx.doi.org/10.5415/apallergy.2020.10.e36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610088PMC
October 2020

Allergic rhinitis as a key factor for the development of gastroesophageal reflux disease in children.

J Microbiol Immunol Infect 2020 Aug 18. Epub 2020 Aug 18.

Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC; Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC; Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan, ROC. Electronic address:

Background: Gastroesophageal reflux disease (GERD) may cause airway symptoms and some airway diseases exacerbate GERD symptoms. Asthma and allergic rhinitis (AR) have been identified as united airway disease because of their similar epidemiology and pathophysiology. Asthma has been considered a risk factor to develop GERD. However, the association between AR and GERD is not clear. We tried to investigate whether AR could increase the development of GERD.

Methods: Children diagnosed as AR without a prior history of GERD were conducted from the National Health Insurance Research Database between 2000 and 2005. After propensity score matching, we enrolled 36,588 children with AR and 36,588 non-AR children as the controls. Cox regression models were adopted to calculate the hazard ratio (HR) of GERD.

Results: AR children had a significantly increased risk of GERD than non-AR children (adjusted HR 1.91, 95% CI = 1.73-2.11, p < 0.001), especially in the age less than 6 years old (adjusted HR 2.68, 95% CI = 1.64-4.38, p < 0.001). The risk factor related to increased risk of GERD including age, gender, and chronic sinusitis.

Conclusion: AR is a risk factor associated with the development of GERD in children.
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http://dx.doi.org/10.1016/j.jmii.2020.08.008DOI Listing
August 2020

Drug hypersensitivity reactions in Asia: regional issues and challenges.

Asia Pac Allergy 2020 Jan 30;10(1):e8. Epub 2020 Jan 30.

Department of Pediatrics, Nippon Medical School, Tokyo, Japan.

There are geographical, regional, and ethnic differences in the phenotypes and endotypes of patients with drug hypersensitivity reactions (DHRs) in different parts of the world. In Asia, aspects of drug hypersensitivity of regional importance include IgE-mediated allergies and T-cell-mediated reactions, including severe cutaneous adverse reactions (SCARs), to beta-lactam antibiotics, antituberculous drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents. Delabeling of low-risk penicillin allergy using direct oral provocation tests without skin tests have been found to be useful where the drug plausibility of the index reaction is low. Genetic risk associations of relevance to Asia include human leucocyte antigen (HLA)-B*1502 with carbamazepine SCAR, and HLA-B*5801 with allopurinol SCAR in some Asian ethnic groups. There remains a lack of safe and accurate diagnostic tests for antituberculous drug allergy, other than relatively high-risk desensitization regimes to first-line antituberculous therapy. NSAID hypersensitivity is common among both adults and children in Asia, with regional differences in phenotype especially among adults. Low dose aspirin desensitization is an important therapeutic modality in individuals with cross-reactive NSAID hypersensitivity and coronary artery disease following percutaneous coronary intervention. Skin testing allows patients with radiocontrast media hypersensitivity to confirm the suspected agent and test for alternatives, especially when contrasted scans are needed for future monitoring of disease relapse or progression, especially cancers.
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http://dx.doi.org/10.5415/apallergy.2020.10.e8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016324PMC
January 2020

Intravenous immunoglobulin therapy enhances suppressive regulatory T cells and decreases innate lymphoid cells in children with immune thrombocytopenia.

Pediatr Blood Cancer 2020 02 17;67(2):e28075. Epub 2019 Nov 17.

Division of Pediatric Hematology-Oncology, Department of Pediatrics, Changhua Christian Children's Hospital, Changhua City, Taiwan.

Background: This study aimed to investigate the relationship between CD4 regulatory T cells (Tregs) and innate lymphoid cells (ILCs) in children with primary immune thrombocytopenia (ITP) undergoing high-dose intravenous immunoglobulin (IVIG) therapy.

Methods: We enrolled a cohort of 30 children with newly diagnosed ITP and 30 healthy controls and collected blood samples for levels of Tregs, ILCs, relevant cytokines, and Treg suppression assay at the diagnosis, two days, four weeks, and one year (only platelet count) after high-dose IVIG treatment. IVIG partial responders was defined by a platelet count less than 100 × 10 /L at 12 months after IVIG treatment.

Results: Children with newly diagnosed ITP exhibited elevated levels of ILC1, ILC2, ILC3, Th17, myeloid dendritic cells (DCs), plasmacytoid DCs, and serum IFN-γ and IL-17A levels, accompanied by a decrease in IL-10-producing Tregs. High-dose IVIG therapy reversed these aberrations. Platelet counts positively correlated with Tregs (rho = 0.72) and negatively correlated with both ILC1 (rho = -0.49) and ILC3 (rho = -0.60) (P < 0.05). Significantly lower Tregs and higher ILC1, ILC3, DCs, and serum IL-17A levels were noted in the partial responders (n = 8) versus responders (n = 22; P < 0.05). We found that Tregs suppressed proliferation of ILCs and CD4 T cells in CD25-depleted peripheral PBMCs and enhanced the apoptosis of CD4 CD45RO T cells in vitro following IVIG therapy.

Conclusions: Effective high-dose IVIG therapy for children with newly diagnosed ITP appears to result in the induction of Tregs, which suppresses ILC proliferation in vitro and is associated with platelet response.
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http://dx.doi.org/10.1002/pbc.28075DOI Listing
February 2020

Nasal nitric oxide is a useful biomarker for acute unilateral maxillary sinusitis in pediatric allergic rhinitis: A prospective observational cohort study.

World Allergy Organ J 2019 17;12(4):100027. Epub 2019 May 17.

School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Background: Nasal nitric oxide (nNO) could be a biomarker for nasal passage inflammation and sinus ostial patency. We have aimed to investigate the nNO concentration and the effect of antibiotic therapy in children with perennial allergic rhinitis (PAR) children with/without acute bacterial sinusitis.

Methods: We enrolled a cohort of 90 and 31 children with PAR, without and with acute unilateral maxillary sinusitis, and 79 normal children. Acute bacterial maxillary sinusitis was diagnosed based on clinical signs and symptoms, radiographic examination and nasal fibroendoscopy. Rhinitis control assessment test (RCAT), rhinomanometry, nNO and fractional exhaled NO (FENO) measurements were performed before and 2 weeks after antibiotic therapy.

Results: We found significantly higher mean nNO levels, FENO values, and total nasal resistance in children with PAR than in normal children ( ​< ​0.05). Acute unilateral maxillary sinusitis was associated with lower lesion-side nNO levels, higher FENO values, total nasal resistance, and poor RCAT scores ( ​< ​0.05). In multivariate analysis, age, IgE, and acute maxillary sinusitis were significant factors influencing nNO levels in children with PAR. The lesion-side nNO levels, FENO values, total nasal resistance, and RCAT scores were reversed after antibiotic therapy ( ​< ​0.05). The lesion-side nNO levels were significantly correlated to nasal obstructive scores ( ​= ​0.59,  ​< ​0.05) and expiratory nasal resistance ( ​= ​-0.54,  ​< ​0.05) in the acute maxillary sinusitis. A cut-off nNO value of 538 ​ppb showed 100% sensitivity and 94.9% specificity, to predict PAR from normal children. An nNO value of 462 ​ppb showed 100% sensitivity and 100% specificity to discriminate between the lesion-side and the unaffected sinus-side in PAR children with acute unilateral maxillary sinusitis.

Conclusions: We conclude that the obstruction of NO from the sinus into the nasal passage is the likely explanation for the decreased lesion-side nNO levels in acute unilateral maxillary sinusitis. nNO is a non-invasive biomarker with high sensitivity to diagnose and monitor treatment responses of PAR patients with acute rhinosinusitis. Both nNO and FENO levels return to baseline following antibiotic therapy, supporting the "one airway one disease" concept.
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http://dx.doi.org/10.1016/j.waojou.2019.100027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526296PMC
May 2019

Allergen-specific immunotherapy enhances CD8  CD25  CD137 regulatory T cells and decreases nasal nitric oxide.

Pediatr Allergy Immunol 2019 08 30;30(5):531-539. Epub 2019 May 30.

Clinical Immunological Center, China Medical University Hospital, College of Medicine, Division of Pediatric Nephrology, China Medical University, Taichung, Taiwan.

Background: 4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8 Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8  CD25  CD137 Treg suppressive function to decrease nasal nitric oxide (nNO) levels.

Methods: Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8  CD25 T cells and suppressive function of CD8  CD25  CD137 Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co-culturing with CD8  CD25  CD137 T cells was analyzed by Western blotting.

Results: Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8 T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8  CD25  CD137 population in PBMCs. Pam3CSK4-stimulated CD8 CD25 CD137 Tregs induced IL-10 and TGF-β and suppressed CD4 CD25- T-cell proliferation mainly by cell contact inhibition. CD8 CD25 CD137 Tregs cultured with nasal epithelial cells suppressed Der p 2-induced iNOS production. Silencing CD137 in sorted CD8 CD25 T cells decreased Pam3CSK4-activated Foxp3 expression.

Conclusion: Der p IT expanded CD8 CD25 CD137 Tregs and decreased nNO levels. Induced CD137 expression on CD8 CD25 Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.
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http://dx.doi.org/10.1111/pai.13061DOI Listing
August 2019

Erratum to "An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity".

J Immunol Res 2019 31;2019:2489429. Epub 2019 Jan 31.

Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou, Keelung, Taiwan.

[This corrects the article DOI: 10.1155/2018/6431694.].
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http://dx.doi.org/10.1155/2019/2489429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374820PMC
January 2019

Increased Type 2 Innate Lymphoid Cells in Patients with Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome.

J Invest Dermatol 2019 08 5;139(8):1722-1731. Epub 2019 Feb 5.

Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan. Electronic address:

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening disorder with an estimated mortality rate of 2%. Recently, type II innate lymphoid cells (ILC2s) have been implicated as an important contributor to the pathogenesis of allergic disorders. However, the roles of ILC2s and ILC2-associated cytokines in DRESS remain unclear. Herein, we enrolled 54 participants (including 24 patients with DRESS syndrome and 30 healthy controls), and identified the increased ST2ILC2s population in skin lesions/blood. In addition, serum soluble ST2 (sST2), IL-5, and TSLP levels were significantly elevated at the acute stage of patients with DRESS. Decreased ILC2s population, serum sST2, and IL-5, accompanied with rash, eosinophilia, and alanine aminotransferase improvement were observed after steroid treatment. In the delayed-responders group (n = 13), serum IL-33, sST2, IL-5, and TSLP levels were significantly increased at the acute phase, but only sST2 levels correlated with alanine aminotransferase and eosinophil improvement at the 4-week follow-up visit. Serum sST2 levels were also correlated with IL-33 (ρ = 0.49; P = 0.02) and alanine aminotransferase levels (ρ = 0.65; P < 0.01) at the onset of DRESS. Our results demonstrated high IL-33/ST2 expression in ILC2 cells plays a role in skin inflammation of drug hypersensitivity, and serum sST2 levels can be as a potential biomarker to predict liver involvement in patients with DRESS syndrome.
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http://dx.doi.org/10.1016/j.jid.2018.10.048DOI Listing
August 2019

Complement regulatory protein CD46 induces autophagy against oxidative stress-mediated apoptosis in normal and asthmatic airway epithelium.

Sci Rep 2018 08 28;8(1):12973. Epub 2018 Aug 28.

Clinical Immunological Center and College of Medicine, China Medical University Hospital, Taichung, Taiwan.

Autophagy plays a major role in defending against oxidative stress in respiratory epithelial cells. The complement regulatory protein CD46 can enhance autophagy and decrease local complement activation at sites of inflammation. This study investigated the mechanism by which CD46 protects against oxidative stress-mediated apoptosis in respiratory epithelium in asthmatic patients. Nasal mucosa samples were obtained from 60 adults with mild asthma who received turbinectomy and 30 controls. A decreased expression of CD46 and increased apoptosis were noted in the damaged nasal epithelium from the asthmatic patients. Primary epithelial cells cultured with Dermatophagoides pteronyssinus 2 showed decreased CD46 and increased cleaved CASPASE-3A expressions. Crosslinking CD46 mAb could induce the formation of autophagosomes and LC3-II expression in primary epithelial cells. CD46 engagement could induce autophagy against hydrogen peroxide-induced epithelial cell death, whereas the autophagy inhibitor 3-methyladenine decreased this effect. In addition, CD46 engagement decreased the expressions of PRO-IL-1β and NLRP3, enhanced the expression of scaffold protein GOPC, and diminished hydrogen peroxide-induced 8-OHdG, IL-1β and IL-6 production. Silencing ATG5 in human lung epithelial A549 cells decreased CD46-activated autophagy with LC3-II. CD46 induced autophagy and decreased the oxidative stress-mediated apoptosis of respiratory epithelium, and this may offer a new therapeutic strategy to treat asthma.
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http://dx.doi.org/10.1038/s41598-018-31317-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113329PMC
August 2018

New Advances in Drug Hypersensitivity Research and Treatment.

J Immunol Res 2018;2018:9345078. Epub 2018 Jun 21.

Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

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http://dx.doi.org/10.1155/2018/9345078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032656PMC
February 2019

Intravenous fish oil containing lipid emulsion attenuates inflammatory cytokines and the development of bronchopulmonary dysplasia in very premature infants: A double-blind, randomized controlled trial.

Clin Nutr 2019 06 18;38(3):1045-1052. Epub 2018 Jun 18.

Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pediatrics, Changhua Christian Children's Hospital, Changhua, Taiwan; School of Medicine, Kaohsiung Medical University, Taiwan. Electronic address:

Background & Aims: Preterm infants have lower levels of long-chain polyunsaturated fatty acids (LCPUFAs). Supplementing very premature infants with intravenous lipid emulsions that fish oil, which is rich in n-3 LC-PUFAs, may decrease bronchopulmonary dysplasia (BPD) by modulating inflammation and neonatal immune function.

Methods: Sixty very low birth weight (VLBW) premature infants requiring ventilator support were randomized in a double-blind manner to 2 groups and received total parenteral nutrition with fish oil containing LE (intervention group, n = 30) or soybean oil containing LE (control group, n = 30) for 7 days. Blood samples and bronchoalveolar lavage fluid (BALF) were obtained for assay on day 1 and 7 days after LE. The primary outcome was to compare the levels of interleukin (IL)-1β and IL-6 in serum and BALF. Secondary outcomes were to compare mortality and co-morbidities.

Results: The levels of IL-1β and IL-6 in serum and BALF were significantly lower in the intervention group at day 8 (p < 0.05). The incidence of BPD in the intervention group compared to the control group was 13.3% versus 36.7% (p = 0.04; odds ratio [OR], 0.36; 95% confidence interval [CI], 0.21-0.86). The duration of ventilator support and oxygen use was significantly less in the intervention group than in the control group (p < 0.05). The level of alanine aminotransferase was significantly lower in the intervention group on day 8 (p = 0.031).

Conclusions: In very premature infants, early administration of fish oil containing LE significantly decreased IL-1β and IL-6 levels in serum and BALF and was associated with shorter duration of ventilator support and less bronchopulmonary dysplasia (BPD).

Trial Registration Number: ISRCTN 11427103.
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http://dx.doi.org/10.1016/j.clnu.2018.06.929DOI Listing
June 2019

An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity.

J Immunol Res 2018 13;2018:6431694. Epub 2018 Feb 13.

Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou, Keelung, Taiwan.

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.
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http://dx.doi.org/10.1155/2018/6431694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830968PMC
September 2018

Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation.

Pulm Pharmacol Ther 2018 02 5;48:37-45. Epub 2017 Oct 5.

School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Research Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3. The expression of type 1 IFN (IFN-α/β) were measured by ELISA. The mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting and chromatin immunoprecipitation. GCS suppressed TLR-induced IFN-α expression, and LABA enhanced the suppressive effect. LABA alone also suppressed TLR-induced IFN-α/β expression, and the effect was reversed by the β2-adrenoreceptor antagonist ICI118551. Dibutyryl-cAMP, a cAMP analog, conferred a similar suppressive effect, and the effect was abrogated by the exchange protein directly activated by cAMP (Epac) inhibitor HJC0197 or intracellular free Ca chelator BAPTA-AM. Formoterol suppressed TLR-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38/ERK. Formoterol suppressed interferon regulatory factor (IRF)-3/IRF-7 expression. Formoterol suppressed CpG-induced translocation of H3K4 specific methyltransferase WDR5 and suppressed H3K4 trimethylation in the IFNA and IFNB gene promoter region. LABA suppressed TLR7/9-induced type 1 IFNs production, at least partly, via the β-adrenoreceptor-cAMP-Epac-Ca, IRF-3/IRF-7, the MAPK-p38/ERK pathway, and epigenetic regulation by suppressing histone H3K4 trimethylation through inhibiting the translocation of WDR5 from cytoplasm to nucleus. LABA may interfere with anti-viral immunity.
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http://dx.doi.org/10.1016/j.pupt.2017.10.004DOI Listing
February 2018

The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3IL-17 T cells.

BMC Nephrol 2017 Jul 10;18(1):225. Epub 2017 Jul 10.

Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.

Background: The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4 forkhead box P3 (FOXP3) T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3IL-17 T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear.

Methods: This study evaluated the roles of the HDAC inhibitor, Treg cells and their differentiation into Th17 cells, which aggravate chronic inflammation and renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model. The study groups included control and UUO mice that were monitored for 7, 14 or 21 days.

Results: Juxtaglomerular (JG) hyperplasia, angiotensin II type 1 receptor (AT1R) expression and lymphocyte infiltration were observed in renal tissues after UUO but were decreased after trichostatin A (TSA) treatment, a HDAC inhibitor. The number of CD4FOXP3 T cells increased progressively, along with the number of FOXP3interleukin (IL)-17 T cells, after 14 days, and their numbers then progressively decreased with increasing CD4IL-17 T cell numbers, as demonstrated by double immunohistochemistry. Progressive renal fibrosis was associated with the loss of CD4FOXP3IL-17 T cells in splenic single-cell suspensions. FOXP3IL-17 T cells expressed TGF-β1 both in vitro and in vivo, and TGF-β1 expression was significantly knockdown by IL-17 siRNA in vitro. These cells were found to play a role in converting Tregs into IL-17- and TGF-β1-producing cells.

Conclusions: TSA treatment decreased JG hyperplasia, the percentage of FOXP3IL-17 cells and the degree of fibrosis, suggesting that therapeutic benefits may result from epigenetic modifications.
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http://dx.doi.org/10.1186/s12882-017-0630-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504832PMC
July 2017

High exhaled nitric oxide levels correlate with nonadherence in acute asthmatic children.

Ann Allergy Asthma Immunol 2017 04;118(4):521-523.e2

Clinical Immunological Center and College of Medicine, China Medical University Hospital, Taichung, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2017.01.031DOI Listing
April 2017

Correlates of Elevated Interleukin-6 and 8-Hydroxy-2'-Deoxyguanosine Levels in Tracheal Aspirates from Very Low Birth Weight Infants Who Develop Bronchopulmonary Dysplasia.

Pediatr Neonatol 2017 02 30;58(1):63-69. Epub 2016 May 30.

Department of Pediatrics, Changhua Christian Children's Hospital, Changhua City, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; School of Medicine, Chung Shan Medical University, Taichung City, Taiwan. Electronic address:

Background: Bronchopulmonary dysplasia (BPD) remains the most common complication of very low birth weight (VLBW) preterm infants, and inflammatory regulation plays a role in the development of the BPD. Interleukin-6 (IL-6) has an important role in airway inflammation and therefore can be used as a marker of airway injury. The study aimed to compare the changes between IL-6 and oxidative stress marker with 8-hydroxy-2'-deoxyguanosine (8-OHdG) from serum and tracheal aspiration (TA) in VLBW preterm infants following development of BPD.

Methods: This birth cohort study enrolled 80 VLBW preterm infants, including 26 who developed BPD. All infants completed the study and survived at 36 weeks postmenstrual age. IL-6 and 8-OHdG concentrations from serum and TA on Day 1 and Day 28 after birth were measured using immunoassay.

Results: IL-6 and 8-OHdG in serum and TA were higher in the BPD group than in the non-BPD group on the 1 day after birth (p < 0.05). The IL-6 and 8-OHdG levels in TA fluid were persistently increased on the 28 day of life in the BPD group (p < 0.05). The TA IL-6 was positively correlated with 8-OHdG levels on the 1 day (r = 0.64, p < 0.05) and 28 day of life (r = 0.76, p < 0.05). Based on receiver operating characteristic curves as a predictor of BPD development, TA IL-6 (cutoff, 456.8 pg/mg) had 81.5% sensitivity and 77.8% specificity, whereas TA 8-OHdG (cutoff, 4.4 ng/mg) had a sensitivity of 81.5% and a specificity of 64.4%.

Conclusion: Persistent inflammation with oxidative DNA damage in the respiratory tract may be a crucial mechanism in BPD.
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http://dx.doi.org/10.1016/j.pedneo.2016.01.004DOI Listing
February 2017

Heat-shock pretreatment reduces expression and release of TSLP from keratinocytes under Th2 environment.

Pediatr Allergy Immunol 2016 Feb 30;27(1):62-9. Epub 2015 Sep 30.

Frontier Molecular Medical Research Center in Children, Changhua Christian Children Hospital, Changhua County, Taiwan.

Background: Atopic dermatitis is a chronic, relapsing inflammatory disease of the skin. Current therapy is not curative, and recalcitrant disease is a big stress and challenge for parents and physicians. This study explored the potential role of heat-shock protein 70 (HSP-70) and its anti-inflammatory effects on keratinocyte under TH2 environment.

Methods: Human keratinocyte cell line (HaCa T) was stimulated with IL-4, IL-13, and TNF-α to synthesize and secrete thymic stromal lymphopoietin (TSLP), an important cytokine of immunopathogenesis in atopic dermatitis. Heat shock was performed by immersing the cell-contained flash into a water bath of 45°C for 20 min. Cell viability, TSLP expression, and secretion of HaCa T cells were measured and compared. Possible regulatory mechanisms influencing the expression of TSLP, such as the STAT6 and NF-κB signal pathways, were investigated.

Results: Heat-shock treatment induced intracellular HSP-70 expression in HaCa T cells without affecting cell viability. The induced expression and secretion of TSLP in HaCa T cells were suppressed by heat shock. The NF-κB signal pathway was inhibited by heat shock, leading to decreased TSLP expression and secretion.

Conclusion: Heat stress-induced HSPs can significantly reduce the production and secretion of TSLP from HaCaT cells under Th2 environment. Thus, the evidence highlights the potential role of HSP-70 for atopic dermatitis in the future.
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http://dx.doi.org/10.1111/pai.12482DOI Listing
February 2016

An increase in CD3+CD4+CD25+ regulatory T cells after administration of umbilical cord-derived mesenchymal stem cells during sepsis.

PLoS One 2014 22;9(10):e110338. Epub 2014 Oct 22.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan.

Sepsis remains an important cause of death worldwide, and vigorous immune responses during sepsis could be beneficial for bacterial clearance but at the price of collateral damage to self tissues. Mesenchymal stem cells (MSCs) have been found to modulate the immune system and attenuate sepsis. In the present study, MSCs derived from bone marrow and umbilical cord were used and compared. With a cecal ligation and puncture (CLP) model, the mechanisms of MSC-mediated immunoregulation during sepsis were studied by determining the changes of circulating inflammation-associated cytokine profiles and peripheral blood mononuclear cells 18 hours after CLP-induced sepsis. In vitro, bone marrow-derived MSCs (BMMSCs) and umbilical cord-derived MSCs (UCMSCs) showed a similar morphology and surface marker expression. UCMSCs had stronger potential for osteogenesis but lower for adipogenesis than BMMSCs. Compared with rats receiving PBS only after CLP, the percentage of circulating CD3+CD4+CD25+ regulatory T (Treg) cells and the ratio of Treg cells/T cells were elevated significantly in rats receiving MSCs. Further experiment regarding Treg cell function demonstrated that the immunosuppressive capacity of Treg cells from rats with CLP-induced sepsis was decreased, but could be restored by administration of MSCs. Compared with rats receiving PBS only after CLP, serum levels of interleukin-6 and tumor necrosis factor-α were significantly lower in rats receiving MSCs after CLP. There were no differences between BMMSCs and UCMSCs. In summary, this work provides the first in vivo evidence that administering BMMSCs or UCMSCs to rats with CLP-induced sepsis could increase circulating CD3+CD4+CD25+ Treg cells and Treg cells/T cells ratio, enhance Treg cell suppressive function, and decrease serum levels of interleukin-6 and tumor necrosis factor-α, suggesting the immunomodulatory association of Treg cells and MSCs during sepsis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110338PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206342PMC
June 2015

Enhanced CD46-induced regulatory T cells suppress allergic inflammation after Dermatophagoides pteronyssinus-specific immunotherapy.

J Allergy Clin Immunol 2014 Nov 25;134(5):1206-9.e1. Epub 2014 Jul 25.

Clinical Immunological Center, China Medical University Hospital, College of Medicine, China Medical University, Taichung, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2014.06.005DOI Listing
November 2014

Urinary 8-hydroxy-2'-deoxyguanosine (8-oxodG) level can predict acute renal damage in young children with urinary tract infection.

Biomarkers 2014 Jun 21;19(4):326-31. Epub 2014 Apr 21.

Departments of Pediatrics .

Background: There are no good biomarkers to predict renal parenchymal involvement in children with urinary tract infection (UTI).

Methods: Children (N = 73) younger than 5 years with UTI were enrolled. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-oxodG) and total antioxidant capacity (TAC) were checked as markers of oxidative stress and antioxidant capacity, respectively. Tc99m-dimercaptosuccinic acid (DMSA) renal scintigraphy was used to find evidence of renal involvement.

Results: Patients with positive DMSA findings had higher levels of urinary 8-oxodG (p = 0.003) and higher urinary TAC (p = 0.001) than patients with normal DMSA findings.

Conclusions: High level of urinary 8-oxodG may be a risk factor of severe renal damage.
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http://dx.doi.org/10.3109/1354750X.2014.910552DOI Listing
June 2014

Hypersensitivity to mosquito bites as the primary clinical manifestation of an Epstein-Barr virus infection.

J Microbiol Immunol Infect 2016 Aug 21;49(4):613-6. Epub 2014 Mar 21.

Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; School of Medicine, Kaohsiung Medicial University, Kaohsiung, Taiwan. Electronic address:

Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by intense local skin reactions with general symptoms, such as high fever and regional lymphadenopathy after mosquito bites. Epstein-Barr virus (EBV) chronic infection and NK cell lymphoproliferative disease have been reported first in diagnosed HMB patients. Here, we present the case of a 6-year-old girl with 2 months' history of bullae and necrotic skin lesions, accompanied by a high temperature, visual hallucinations, and liver dysfunction after mosquito bites. A histopathologic examination of the skin lesion showed vasculitis and EBV infection. We could not detect any findings of hematologic malignancies or NK cell proliferative disease in the patient. Clinicians should closely evaluate HMB patients for possible development of lymphoproliferative status or hematologic malignant disorders.
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http://dx.doi.org/10.1016/j.jmii.2014.01.008DOI Listing
August 2016

CD8⁺ Treg cells associated with decreasing disease activity after intravenous methylprednisolone pulse therapy in lupus nephritis with heavy proteinuria.

PLoS One 2014 27;9(1):e81344. Epub 2014 Jan 27.

Division of Pediatric Nephrology, China Medical University Hospital, Taichung, Taiwan ; Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan ; College of Medicine, China Medical University, Taichung, Taiwan.

Unlabelled: We focus on the role of CD8(+) Treg cell in Intravenous methyl-prednisolone (IVMP) pulse therapy in forty patients with active Class III/IV childhood lupus nephritis (LN) with heavy proteinuria. IVMP therapy for five days. From peripheral blood mononuclear cells (PBMCs) and renal tissues, we saw IVMP therapy definitely restoring both CD4(+)CD25(+)FoxP3(+) and CD8(+)CD25(+)Foxp3(+) Treg cell number plus greater expression with intracellular IL-10 and granzyme B in CD8(+)FoxP3(+) Treg from PBMCs. IVMP-treated CD8(+)CD25(+) Treg cells directly suppressed CD4(+) T proliferation and induced CD4(+)CD45RO(+) apoptosis. Histologically, CD4(+)FoxP3(+) as well as CD8(+)FoxP3(+) Treg cells appeared in renal tissue of LN patients before IVMP by double immunohistochemical stain. CD8(+)FoxP3(+) Treg cells increased in 10 follow-up renal biopsy specimens after IVMP. Reverse correlation of serum anti-C1q antibody and FoxP3(+) Treg cells in PBMNCs (r = -0.714, P<0.01). After IVMP, serum anti-C1q antibody decrease accompanied increase of CD4(+)FoxP3(+) Treg cells. CD8(+)Treg cells reduced interferon-r response in PBMCs to major peptide autoepitopes from nucleosomes after IVMP therapy; siRNA of FoxP3 suppressed granzyme B expression while decreasing CD8(+)CD25(+)Treg-induced CD4(+)CD45RO(+) apoptosis. Renal activity of LN by SLEDAI-2k in childhood LN was significantly higher than two weeks after IVMP (P<0.01). CD8(+)FoxP3(+) Treg cells return in post-IVMP therapy and exert crucial immune modulatory effect to control autoimmune response in LN.

Trial Registration: DMR97-IRB-259.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081344PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903465PMC
November 2014

Functional defects of CD46-induced regulatory T cells to suppress airway inflammation in mite allergic asthma.

Lab Invest 2012 Sep 2;92(9):1260-9. Epub 2012 Jul 2.

Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan.

Defective recruitment of regulatory T cells (Treg) function to the airway is important in the pathogenesis of allergic asthma. Complement regulatory protein (CD46) is a newly defined costimulatory molecule for Treg activation, which together with IL-10/granzyme B production may aid in suppressing asthmatic inflammation. This study examines chemotaxis and adhesion molecule expression on CD3/CD46-activated CD4(+) T cells (Tregs) from patients with and without asthma to suppress mite allergen-induced respiratory epithelial cells inflammation and to elucidate the mechanism of CD46-mediated Treg activation. Diminished IL-10/granzyme B and CCR4 expression from CD3/CD46-activated Tregs appeared in asthmatic subjects. CD3/CD46-activated Tregs from asthma patients co-cultured with BEAS-2B cells suppressed Dermatophagoides pteronyssinus 2 induced nuclear factor-κB/p65 by cell contact inhibition. Decreased interaction of CD3/CD46-mediated Tregs and BEAS-2B cells from asthmatics was associated with downregulated phosphorylation of protein kinase B (AKT) expression. Results provide the first evidence that decreased interaction between CD46-mediated Tregs and lung epithelial cells with less IL-10/granzyme B production may cause airway inflammation in allergic asthma.
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http://dx.doi.org/10.1038/labinvest.2012.86DOI Listing
September 2012

Significant factors associated with severity and outcome of an initial episode of acute urticaria in children.

Pediatr Allergy Immunol 2010 Nov;21(7):1043-51

Department of Dermatology, Changhua Christian Hospital, Changhua, Taiwan.

The aim of this study was to determine the predictive factors of severity and duration of an initial episode of acute urticaria in children. This was a retrospective study of 1120 children of <18 yr who presented to the emergency department (ED) with an initial episode of acute urticaria during the period January 1, 2001, to December 31, 2007. These patients were followed in the ED or outpatient department (OPD) until their symptoms subsided. Variables comprising mild, moderate, and severe urticaria were compared to determine the predictors of severity. The relationships between duration of urticaria and clinical features, including physician-diagnosed causes and treatment modalities, were also analyzed. Significant predictive factors of severity of an initial episode of acute urticaria in children included age, physician-diagnosed causes of urticaria, clinical presentation, coexistent pyrexia or angioedema, and personal allergic history (all p < 0.001). The duration of urticaria was dependent on the physician-diagnosed causes and treatment. Inhalants and unknown causes were predictive of longer duration, while contact materials were associated with shorter duration of urticaria (p < 0.001). Combination treatment comprising an oral plus injectable form of antihistamine or corticosteroid significantly shortened the duration of urticaria compared to single treatment (p < 0.001), especially in children receiving short-term aggressive treatment in the pediatric observation unit (POU) of the ED.
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http://dx.doi.org/10.1111/j.1399-3038.2010.01070.xDOI Listing
November 2010

TLR2 agonists enhance CD8+Foxp3+ regulatory T cells and suppress Th2 immune responses during allergen immunotherapy.

J Immunol 2010 Jun 7;184(12):7229-37. Epub 2010 May 7.

Department of Pediatrics, Changhua Christian Hospital and Institute of Clinical Medicine, National Ynag-Ming University, Taipei, Taiwan, Republic of China.

Pam3CSK4, a synthetic TLR2 ligand, has been shown to expand CD4+ regulatory T cells (Treg cells). Less is known about the function of CD8+ Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy (IT). This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8+CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population. PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times: before IT and 6 mo and 1 y after the maximum-tolerated dose. This study was performed without a placebo-controlled group. D. pteronyssinus-specific IT induced a significant increase in CD8+Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production. Pam3CSK4-treated CD8+CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition. TUNEL revealed that CD8+CD25+ Treg cells, but not CD4+CD25+ Treg cells, directly induced CD4+CD45ROhi+ apoptosis. Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells; therefore, it may be a good adjuvant for the treatment of mite allergies.
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http://dx.doi.org/10.4049/jimmunol.1000083DOI Listing
June 2010

Induction of IL-10+ CD4+ CD25+ regulatory T cells with decreased NF-κB expression during immunotherapy.

Pediatr Allergy Immunol 2010 Feb 13;21(1 Pt 2):e166-73. Epub 2009 Aug 13.

Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan.

MyD88 is a major toll-like receptor (TLR) adaptor to activate NF-κB, which acts as a mater switch for allergic inflammation disease. Sterile hust dust extracts have been reported with TLR-dependent immunostimulatory activities. The aim of this study was to evaluate whether Dermatophagoides pteronyssinus (Der p) immunotherapy may increase IL-10+ CD4+ CD25+ T cells with modulating MyD88 signaling proteins, to decrease NF-κB expression. Peripheral blood mononuclear cells were isolated from patients before and after 1 yr of Der p immunotherapy, and also from matched control subjects. After 2 days of Der p-2 stimulation, intracellular IL-10 and Foxp3 expression of CD4(+) CD25(+) T cells were measured by flow-cytometry. The expression of IL-1 receptor-associated kinase (IRAK)-1 in cytoplasm and IFN-regulator factor-3 (IRF-3) with NF-κB/p65 in nuclei was determined by Western-blot analysis. Patients undergoing immunotherapy produced more soluble CD14, IL-10, and TGF-β that correlated with FEV(1) improvement (p < 0.05). In the immunotherapy group, the number of Foxp3+ CD4+ Treg cells increased more than the baseline status (25.06 ± 4.19 vs. 16.08 ± 3.54, p < 0.05). Additionally, increased IL-10 production with decreased IRAK-1 and NF-κB/p65 nuclear translocation was observed in sorted-purified Treg cells. IL-10(+) CD4(+) CD25(+) Treg cells may respond to Der p-2 and down-regulate NF-κB/p65 expression to maintain immune tolerance during immunotherapy.
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http://dx.doi.org/10.1111/j.1399-3038.2009.00870.xDOI Listing
February 2010

Comparison of the effects of nebulized terbutaline with or without intravenous betamethasone on exhaled nitric oxide in children with acute asthma attack.

J Microbiol Immunol Infect 2006 Feb;39(1):33-8

Department of Pediatrics, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background And Purpose: Exhaled nitric oxide (eNO), a non-invasive marker that reflects the degree of airway inflammation, may be useful for assessing the response to anti-inflammatory treatment of asthma. The purpose of this randomized prospective study was to compare the effect of a nebulized terbutaline plus a single intravenous dose of betamethasone at baseline followed by a second of terbutaline at 6 h with the effect of the same protocol of nebulized terbutaline alone on airway inflammation of acute asthmatic children as demonstrated by eNO levels.

Methods: Children visiting the emergency department due to acute asthma attack were recruited. All enrolled patients had fluorescent assay-proven hypersensitivity to Dermatophagoides pteronyssinus. Patients were randomized to receive either nebulized terbutaline plus intravenous betamethasone (experimental group, n = 11) or nebulized terbutaline alone (control group, n = 11) at baseline followed by a second dose of nebulized terbutaline alone 6 h later.

Results: Exhaled NO concentrations were significantly reduced in the experimental group at 7 h (40.25 +/- 12.43 vs 28.88 +/- 18.02 ppb; p = 0.005) and 12 h (40.25 +/- 12.43 vs 30.11 +/- 18.16 ppb; p = 0.007) after treatment. The eNO level in the experimental group was also reduced at 7 h (28.88 +/- 18.02 vs 38.12 +/- 16.50 ppb; p = 0.034) and 12 h (30.11 +/- 18.16 vs 39.36 +/- 17.63 ppb; p = 0.035) compared to the control group. The change of eNO concentration was correlated to the change of peak expiratory flow rate (PEFR) [r = -0.678; p = 0.022] and pulmonary index scores (r = 0.606; p = 0.048) at 7 h after treatment in the betamethasone group.

Conclusion: Nebulized terbutaline given at baseline and 6 h later was significantly more effective in improving PEFR and asthmatic symptoms (pulmonary index scores) for at least 12 h when the initial dose was administered in combination with intravenous betamethasone.
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February 2006

Induced apoptosis of TH2 lymphocytes in asthmatic children treated with Dermatophagoides pteronyssinus immunotherapy.

Pediatr Allergy Immunol 2005 Nov;16(7):602-8

Department of Pediatrics, Children's Hospital, Changhua Christian Hospital, Institute of Medical Research, Chang Jung Christian University, Changhua, Taiwan.

Allergen-specific immunotherapy (IT) has been effectively used for the treatment of asthma. Allergen specific IT induced immune tolerance with induction of TH2 cells anergy remain to be clarified. The aim of this study was to evaluate whether the mite allergen Dermatophagoides pteronyssinus (Dpt) specific IT serially decreased IL-4+/CD4+ (TH2) lymphocytes and induced apoptosis of TH2 lymphocytes in asthmatic children. Sixty Dpt-sensitive asthmatic children were randomly assigned to a received IT and an untreated group. Dermatophagoides pteronyssinus specific IT treated patients were examined at three time points: before IT, after 6 months of an increased dose phase and with maximum tolerated doses after 1 yr. Peripheral blood mononuclear cells (PBMC) were isolated and cultured for 48 h for cellular staining with CD4+, CD45RO cell phenotypes and interleukin (IL)-4 and interferon-gamma expression by fluorescence monoclonal antibodies. Apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) method. A simultaneous flow cytometric study using the same permeabilized cell was examined to determine whether apoptosis occurred preferentially in TH2 lymphocytes. The data demonstrated that Dpt specific IT decreased Dpt-specific IgE levels (p < 0.01) after 1 yr of treatment. In addition, decreased CD4+IL-4+ TH2 cells with increased CD4+IFN-gamma+ TH(1) cells were observed at 6 months and 1 yr after IT treatment (p < 0.05). At the same time, apoptosis of CD4+IL-4+ TH2 lymphocytes in the IT group had increased after 1 yr of treatment when compared with the results before treatment (p < 0.001) and after 6 months of treatment (p = 0.046). In addition, CD45RO cells apoptosis mainly occurred after 6 months of IT treatment and after 1-year period of IT treatment (p < 0.05). All of the data suggested that Dpt specific IT decreased Dpt specific IgE and CD4+IL-4+ TH2 lymphocytes with induction apoptosis of CD4+IL-4+ TH2 lymphocytes subsets serially.
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http://dx.doi.org/10.1111/j.1399-3038.2005.00313.xDOI Listing
November 2005
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