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1.
J Asthma ; : 1-10, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32375555

RESUMO

Objective: Omalizumab is more effective in severe allergic patients with eosinophilic asthma than those with non-eosinophilic asthma. IL-18, a unique cytokine involved in allergic but non-eosinophilic inflammation, might be associated with the latter condition. We aimed to clarify the roles of IL-18 related pathways in insufficient response to omalizumab treatment.Methods: Patients with severe allergic asthma who completed 2-year omalizumab treatments at Kyoto University Hospital were included in this study (UMIN000002389). Associations between pretreatment levels of serum free IL-18 in addition to other mediators and asthma phenotypes including responses to omalizumab treatment were analyzed. Changes in serum free IL-18, periostin and total IgE levels during the treatment were also examined.Results: Twenty-seven patients (19 females, average age of 55.7 years) were examined. Fifteen incomplete responders who experienced exacerbations in the second year, were significantly and more frequently obese and showed significantly earlier asthma onset, lower blood eosinophils and more exacerbations before omalizumab treatment than complete responders. Significantly more patients showed high baseline serum free IL-18 levels (≥141 pg/mL, a threshold for the highest tertile) among the incomplete responders than complete responders. Patients with high serum free IL-18 levels shared similar characteristics with incomplete responders, showing significant reductions in serum total IgE levels during omalizumab treatment. Finally, serum free IL-18 levels negatively correlated with serum periostin levels at baseline and in change ratios.Conclusions: High baseline serum free IL-18 levels may predict reduced omalizumab efficacy in severe allergic patients with type-2 low asthma, regarding reduction of exacerbations.

2.
Allergol Int ; 69(2): 165-166, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32241532
3.
Artigo em Inglês | MEDLINE | ID: mdl-32142372

RESUMO

RATIONALE: Aspirin-exacerbated respiratory disease is characterized by severe asthma, non-steroidal anti-inflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin-hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner. OBJECTIVES: To evaluate omalizumab efficacy against aspirin-hypersensitivity, leukotriene E4 overproduction, and symptoms during oral aspirin challenge in aspirin-exacerbated respiratory disease using a randomized design. METHODS: We performed a double-blind, randomized, cross-over, placebo-controlled, single-centre study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients aged 20-79 years with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to 3-month treatment with omalizumab or placebo, followed by >18-week washout period (cross-over design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration vs time curve in the intention-to-treat population during oral aspirin challenge. MEASUREMENTS AND MAIN RESULTS: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration vs time curve during oral aspirin challenge in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) was significantly lower compared with the placebo phase (80.8 [interquartile range, 65.4-87.8]) (p<0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (p<0.001). CONCLUSIONS: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during oral aspirin challenge, resulting in aspirin tolerance in 62.5% of aspirin-exacerbated respiratory disease patients. Clinical trial registration available at https://www.umin.ac.jp/ctr/index.htm, ID: UMIN000018777. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

4.
Allergol Int ; 69(2): 187-196, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32007360

RESUMO

Interleukin (IL)-4 and IL-13, signature type 2 cytokines, exert their actions by binding to two types of receptors sharing the IL-4R α chain (IL-4Rα). Since IL-4 and IL-13 play important and redundant roles in the pathogenesis of allergic diseases, blocking both the IL-4 and IL-13 signals would be a powerful and effective strategy for treating allergic diseases. Dupilumab (Dupixent®) is a fully human monoclonal antibody recognizing IL-4Rα and blocking both the IL-4 and IL-13 signals. Dupilumab was first prescribed for atopic dermatitis (AD) patients and has been widely approved for adult patients with moderate to severe AD since 2018. Dupilumab has since been used for asthma, receiving approval for uncontrolled asthma in 2019. A phase 3 study using dupilumab for chronic rhinosinusitis with nasal polyps (CRSwNP) has been just completed, with positive results. Several clinical trials of dupilumab for other diseases in which type 2 inflammation is dominant are now underway. It is hoped that dupilumab will open the door to a new era for treating allergic patients with AD, asthma, and CRSwNP, and for more patients with type 2 inflammations.

5.
Respir Res ; 21(1): 38, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000779

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a median survival of only three to 5 years. Fibroblast proliferation is a hallmark of IPF as is secretion of extracellular matrix proteins from fibroblasts. However, it is still uncertain how IPF fibroblasts acquire the ability to progressively proliferate. Periostin is a matricellular protein highly expressed in the lung tissues of IPF patients, playing a critical role in the pathogenesis of pulmonary fibrosis. However, it remains undetermined whether periostin affects lung fibroblast proliferation. METHODS: In this study, we first aimed at identifying periostin-dependently expressed genes in lung fibroblasts using DNA microarrays. We then examined whether expression of cyclins and CDKs controlling cell cycle progression occur in a periostin-dependent manner. We next examined whether downregulation of cell proliferation-promoting genes by knockdown of periostin or integrin, a periostin receptor, using siRNA, is reflected in the cell proliferation of lung fibroblasts. We then looked at whether lung fibroblasts derived from IPF patients also require periostin for maximum proliferation. We finally investigated whether CP4715, a potent inhibitor against integrin αVß3 (a periostin receptor), which we have recently found blocks TGF-ß signaling, followed by reduced BLM-induced pulmonary fibrosis in mice, can block proliferation of lung fibroblasts derived from IPF patients. RESULTS: Many cell-cycle-related genes are involved in the upregulated or downregulated genes by periostin knockdown. We confirmed that in lung fibroblasts, periostin silencing downregulates expression of several cell-cycle-related molecules, including the cyclin, CDK, and, E2F families, as well as transcription factors such as B-MYB and FOXM1. Periostin or integrin silencing slowed proliferation of lung fibroblasts and periostin silencing increased the distribution of the G0/G1 phase, whereas the distribution of the G2/M phase was decreased. Lung fibroblasts derived from IPF patients also required periostin for maximum proliferation. Moreover, CP4715 downregulated proliferation along with expression of cell-cycle-related genes in IPF lung fibroblasts as well as in normal lung fibroblasts. CONCLUSIONS: Periostin plays a critical role in the proliferation of lung fibroblasts and the present results provide us a solid basis for considering inhibitors of the periostin/integrin αVß3 interaction for the treatment of IPF patients.

6.
Allergol Int ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31952913

RESUMO

BACKGROUND: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS. METHODS: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence. RESULTS: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin. CONCLUSIONS: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence.

7.
Allergol Int ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31980374

RESUMO

Interleukin (IL)-24 is a member of the IL-20 family of cytokines and is produced by various types of cells, such as CD4+ T cells, NK cells, mast cells, keratinocytes, bronchial epithelial cells, and myofibroblasts. Previous studies suggest that IL-24 plays an essential role in the pathogenesis of pro-inflammatory autoimmune disorders such as psoriasis, arthritis, and inflammatory bowel diseases. However, the role of IL-24 in the pathogenesis of allergic diseases has been elusive. It has already been reported that IL-24 is involved in the pathogenesis of allergic lung and skin diseases. Moreover, we have recently revealed for the first time the pivotal functions of IL-24 in IL-13-mediated skin barrier dysfunction in atopic dermatitis (AD), which is known to be a characteristic of AD caused by Th2 cytokines such as IL-4 or IL-13. In this review, we show recent advances in the basic characteristics of IL-24 and its novel functions in the pathogenesis of allergic skin inflammation, focusing on AD. A better understanding of the role of IL-24 in allergic diseases can lead to the development of new therapeutic options.

8.
Am J Respir Cell Mol Biol ; 62(2): 204-216, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31505128

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to learn whether the cross-talk between TGF-ß (transforming growth factor-ß), a central mediator in pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether inhibitors for integrin αVß3, a periostin receptor, can block pulmonary fibrosis in model mice and the TGF-ß signals in fibroblasts from patients with IPF. We found that cross-talk exists between TGF-ß and periostin signals via αVß3/ß5 converging into Smad3. This cross-talk is necessary for the expression of TGF-ß downstream effector molecules important for pulmonary fibrosis. Moreover, we identified several potent integrin low-molecular-weight inhibitors capable of blocking cross-talk with TGF-ß signaling. One of the compounds, CP4715, attenuated bleomycin-induced pulmonary fibrosis in vivo in mice and the TGF-ß signals in vitro in fibroblasts from patients with IPF. These results suggest that the cross-talk between TGF-ß and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block this cross-talk.

9.
Allergol Int ; 69(1): 111-120, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31272904

RESUMO

BACKGROUND: Periostin is a matricellular protein belonging to the fasciclin family, playing a role for the pathogenesis of allergic diseases by binding to integrins on cell surfaces. Serum periostin is elevated in various allergic diseases reflecting type 2 inflammation and tissue remodeling so that for allergic diseases, periostin is expected to be a novel biomarker for diagnosis, assessing severity or prognosis, and predicting responsiveness to treatments. We have previously shown that most serum periostin exists in the oligomeric form by intermolecular disulfide bonds. METHODS: In this study, we examined how periostin forms a complex in serum, whether the periostin complex in serum is functional, and whether the complex formation interferes with reactivity to anti-periostin Abs. RESULTS: We found that periostin formed a complex with IgA1 at a 1:1 ratio. The periostin in the serum complex contained at least five different isoforms. However, IgA was not essential for the oligomeric formation of periostin in mouse serum or in IgA-lacking serum. The periostin-IgA complex in human serum was functional, sustaining the ability to bind to αVß3 integrin on cell surfaces. Moreover, periostin formed the complex with IgA broadly, which interferes the binding of the Abs recognizing all of the domains except the R4 domain to periostin. CONCLUSIONS: Periostin is a novel member of the IgA-associated molecules. These results are of great potential use to understand the pathological roles of periostin in allergic diseases and, from a practical standpoint, to develop diagnostics or therapeutic agents against periostin.

12.
Int Arch Allergy Immunol ; 180(3): 195-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31505505

RESUMO

BACKGROUND: Previous studies have used serum periostin levels as a biomarker of Th2-driven inflammatory responses. However, no population-based study has yet examined the association of serum periostin levels with the allergic status of children. OBJECTIVES: The aim of this study was to determine the usefulness of periostin as a biomarker for allergy in a group of 7-year-old Korean children. METHOD: This prospective cross-sectional study examined 451 children (aged 7 years to 7 years and 11 months) from the general pediatric population who attended 6 different schools between June and July 2016. A total of 249 children, all of whom completed the questionnaire and skin prick test and provided blood samples, were included in the final analysis. RESULTS: The geometric mean serum periostin level was 107.6 ng/mL (95% CI 104.5-110.7). After adjustment for confounding, serum periostin levels were significantly associated with sensitization to poly-allergens (adjusted odds ratio, aOR 1.032, 95% CI 1.006-1.059, p = 0.016) and pollen (aOR 1.020, 95% CI 1.002-1.039, p = 0.026). Serum periostin levels were also associated with eosinophil levels (adjusted ß = 0.023, SE = 0.009, p = 0.010), but were unrelated to body mass index, sex, obesity, or presence of an allergic disease. CONCLUSIONS: Our results suggest thatserum periostin level may have limited usefulness as a biomarker of allergic disease in children.


Assuntos
Biomarcadores/sangue , Moléculas de Adesão Celular/sangue , Eosinófilos/imunologia , Hipersensibilidade/diagnóstico , Imunização/estatística & dados numéricos , Alérgenos/imunologia , Criança , Estudos Transversais , Feminino , Humanos , Hipersensibilidade/epidemiologia , Coreia (Geográfico)/epidemiologia , Masculino , Grupos Populacionais , Estudos Prospectivos , Testes Cutâneos
13.
J Dermatol Sci ; 95(2): 70-75, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31378660

RESUMO

BACKGROUND: We sometimes encounter difficulties in assessing the severity of pediatric atopic dermatitis (AD) using currently available biomarkers such as thymus and activation-regulated chemokine (TARC) due to the higher baseline values in non-AD children. Recent case control studies have indicated the usefulness of squamous cell carcinoma antigens (SCCAs) in pediatric and adult AD. Notably, SCCAs are induced by IL-4 and IL-13, vital Th2 cytokines that play important roles in AD etiology. OBJECTIVES: Relatively low prevalence and mild disease severity of pediatric AD are observed in our Ishigaki cohort presumably due to the moisturising subtropical climate, which could conversely mean possible higher allergic potential of non-AD subjects towards AD. Thus, the purpose of this study was to further investigate the feasibility of using SCCAs together with TARC and periostin as biomarkers for pediatric AD even in the Ishigaki cohort. METHODS: We enrolled 1459 nursery school children and identified 96 as having AD through 2009-2011. As statistical analyses, we performed Student's t-test, correlation analysis, and receiver and operating characteristic (ROC) analysis. RESULTS: Serum SCCA1, SCCA2, periostin and TARC levels were all significantly increased in AD compared with those in non-AD, but only serum SCCA2 showed a significant increase in AD when assessed in each age group or in subgroup analysis. Among the biomarkers tested, serum SCCA2 also showed the best correlations with clinical AD severity and TARC and showed the best diagnosability for AD in ROC analysis. CONCLUSIONS: SCCA2 is a potent biomarker for pediatric AD in the Ishigaki cohort.

15.
Otol Neurotol ; 40(8): e820-e823, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31348135

RESUMO

OBJECTIVES: The aim of this article was to investigate the effectiveness and underlying mechanisms of OK-432 therapy in patients with auricular hematomas. STUDY DESIGN AND SETTING: Case series with planned data collection. SUBJECTS AND METHODS: We tried this therapy in 47 patients with auricular hematoma between April 2008 and August 2018. We aspirated as much of the fluid content of each lesion as possible with a 21-gage needle. We injected OK-432 solution into the lesion with the same needle that we used for aspiration. We performed this treatment at an outpatient basis without hospitalization. RESULTS: Disappearance and marked reduction of the lesion were observed in all patients who had this therapy, and local scarring and deformity of the auricle did not occur in any patients. As adverse effects, local pain at the injection site and fever (37-38.5°C) were observed in some cases of the patients who had this therapy. The concentrations of various cytokines in each aspirate before and after OK-432 therapy were investigated. The production of tumor necrosis factor-α, interleukin-6, interleukin-8, interferon gamma, vascular endothelial growth factor, and periostin was significantly elevated in the aspirate fluid after OK-432 therapy. CONCLUSION: OK-432 therapy is simple, easy, safe, effective, and can be used as a substitute for surgery in the treatment of auricular hematoma.

16.
Int J Mol Sci ; 20(11)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167385

RESUMO

The prevalence rates of allergic diseases are increasing worldwide, particularly in industrial countries. To date, many mouse models have been generated for allergy research; studies conducted using these models have suggested the importance of cross-talk between immune cells and tissue-resident non-immune cells in the onset of allergic diseases. However, there are several differences between the immune systems of rodents and humans, and human studies are limited. Thus, mice reconstituted with human immune cells are a novel tool for the preclinical evaluation of the efficacy and safety of developing drugs. Genetic technologies for generating humanized mice have improved markedly in recent years. In this review, we will discuss recent progress in allergy research using humanized mice and introduce our recent humanized mouse model of airway inflammation in human immune cells.


Assuntos
Hipersensibilidade/imunologia , Pesquisa , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Camundongos , Camundongos Transgênicos
17.
Adv Exp Med Biol ; 1132: 79-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037627

RESUMO

The primarily pathogenesis of IPF, an incurable respiratory disease is believed to over-repair to lung injury. The development of new drugs for IPF has increased the necessity of identifying biomarkers for predicting clinical behavior and the selection of the appropriate treatment strategy for individual patient.We and another group found that periostin, a matricellular protein expressed specifically in areas of ongoing fibrotic lesions, such as fibroblastic foci in lung tissues from human IPF or murine bleomycin-induced lung injury models. Murine bleomycin-induced lung injury was improved by the constant suppression of periostin expression and treatment with neutralizing anti-periostin antibodies at the fibroproliferative phase. Moreover, total periostin can predict both short-term declines of pulmonary function and overall survival in IPF patients. Our group also established a new enzyme-linked immunosorbent assay (ELISA) kit that is more specific for IPF compared with the conventional kit. This new periostin ELISA kit specifically detects monomeric form, whereas the conventional kit detects both monomeric and oligomeric forms. The monomeric periostin levels can be used to predict pulmonary function decline and to distinguish IPF patients from healthy controls.In conclusion, periostin may play an important role in fibrogenesis and could be a potential biomarker for predicting disease progression and therapeutic effect in IPF patients.


Assuntos
Moléculas de Adesão Celular/análise , Fibrose Pulmonar Idiopática/diagnóstico , Animais , Biomarcadores/análise , Bleomicina , Fibroblastos , Humanos , Pulmão/patologia , Camundongos
18.
Allergy ; 74(5): 855-873, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31095767

RESUMO

Allergen immunotherapy (AIT) has been in use for the treatment of allergic disease for more than 100 years. Asthma treatment relies mainly on corticosteroids and other controllers recommended to achieve and maintain asthma control, prevent exacerbations, and improve quality of life. AIT is underused in asthma, both in children and in adults. Notably, patients with allergic asthma not adequately controlled on pharmacotherapy (including biologics) represent an unmet health need. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence-based recommendations for the use of house dust mites (HDM) AIT as add-on treatment for HDM-driven allergic asthma. This guideline was developed by a multi-disciplinary working group using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. HDM AIT was separately evaluated by route of administration and children and adults: subcutaneous (SCIT) and sublingual AIT (SLIT), drops, and tablets. Recommendations were formulated for each. The important prerequisites for successful treatment with HDM AIT are (a) selection of patients most likely to respond to AIT and (b) use of allergen extracts and desensitization protocols of proven efficacy. To date, only AIT with HDM SLIT-tablet has demonstrated a robust effect in adults for critical end points (exacerbations, asthma control, and safety). Thus, it is recommended as an add-on to regular asthma therapy for adults with controlled or partially controlled HDM-driven allergic asthma (conditional recommendation, moderate-quality evidence). HDM SCIT is recommended for adults and children, and SLIT drops are recommended for children with controlled HDM-driven allergic asthma as the add-on to regular asthma therapy to decrease symptoms and medication needs (conditional recommendation, low-quality evidence).

19.
Medicina (Kaunas) ; 55(5)2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108995

RESUMO

Background: Antifibrotic agents have been approved for the treatment of idiopathic pulmonary fibrosis (IPF). However, the efficacy of these drugs in the treatment of familial IPF (FIPF) has not been previously reported. Case presentation: We report the case of a 77-year-old man with FIPF, successfully treated with pirfenidone. His uncle died due to IPF, and his niece was diagnosed with the disease. He had worsening dyspnea two months prior to admission to our hospital. Upon admission, he had desaturation when exercising and broad interstitial pneumonia. Administration of pirfenidone improved his dyspnea, desaturation, and the reticular shadow on his chest radiograph. Increased fibrotic marker levels KL-6 and SP-D were also normalized in six months; treatment had no effect on his serum periostin level. Pirfenidone has been effective for over two years. Conclusion: Antifibrotic agents such as pirfenidone may be useful for the management of FIPF, as well as cases of sporadic IPF.


Assuntos
Moléculas de Adesão Celular/análise , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas/farmacologia , Idoso , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Moléculas de Adesão Celular/sangue , Tosse/etiologia , Progressão da Doença , Dispneia/etiologia , Humanos , Masculino , Mucina-1/análise , Mucina-1/sangue , Proteína A Associada a Surfactante Pulmonar/análise , Proteína A Associada a Surfactante Pulmonar/sangue , Proteína D Associada a Surfactante Pulmonar/análise , Proteína D Associada a Surfactante Pulmonar/sangue , Piridonas/uso terapêutico
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