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Abstract ETS homologous factor (EHF) belongs to the epithelium-specific subfamily of the E26 transformation-specific (ETS) transcription factor family. Currently, little is known about EHF’s function in cancer. We previously reported that ETS1 induces expression of the ZEB family proteins ZEB1/δEF1 and ZEB2/SIP1, which are key regulators of the epithelial–mesenchymal transition (EMT), by activating the ZEB1 promoters. We have found that EHF gene produces two transcript variants, namely a long form variant that includes exon 1 (EHF-LF) and a short form variant that excludes exon 1 (EHF-SF). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting the EMT phenotypes of cancer cells. Most importantly, we identified a novel point mutation within the conserved ETS domain of EHF, and found that EHF mutations abolish its original function while causing the EHF protein to act as a potential dominant negative, thereby enhancing metastasis in vivo. Therefore, we suggest that EHF acts as an anti-EMT factor by inhibiting the expression of ZEBs, and that EHF mutations exacerbate cancer progression.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today.To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Background: There have been no studies of dual administration of sublingual immunotherapy (SLIT) tablets for perennial and seasonal allergic rhinitis. This trial (JapicCTI-184014) was conducted to investigate the safety profile and immunological response during dual therapy with SQ house dust mite (HDM) and Japanese cedar pollen (JCP) SLIT tablets. Methods: This was a multicenter, open-label, randomized trial of 109 Japanese patients with coexisting HDM and JCP allergic rhinitis who had positive tests for HDM- and JCP specific IgE (≥0.7 kU/L). Patients were allocated to receive HDM (N = 54) or JCP (N = 55) SLIT tablets alone for 4 weeks followed by 8 weeks of dual therapy with both SLIT tablets administered within 5 min of each other. Adverse events (AEs), adverse drug reactions (ADRs), and serum IgE and IgG4 specific for HDM (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and JCP were recorded. Results: The percentage of subjects with AEs and ADRs was similar between the two groups and between the two periods of monotherapy and dual therapy. Most AEs and ADRs were mild in severity, and no serious events were observed. The most common ADRs were local events in the oral cavity. Levels of IgE and IgG4 specific for HDM (D. farinae, D. pteronyssinus) and JCP were increased after treatment with HDM and JCP SLIT tablets, respectively. Conclusions: Dual therapy with both SLIT tablets administered within 5 min after 4 weeks of monotherapy with HDM or JCP tablet was well tolerated and induced the expected immunological responses. Keywords: Allergic rhinitis, Dual therapy, Immunological response, Safety, Sublingual immunotherapy

Background: Clinical efficacy of allergen-specific Immunotherapy (AIT) towards Japanese cedar (JC) pollen allergy is firmly established but JC pollen-specific biomarker assays are lacking. Treatment-related increase of allergen-specific antibodies is a robust biomarker of successful AIT. Allergen-specific non-IgE antibodies are believed to reduce the effects of allergen exposure by competing with IgE for allergen binding, and in-vitro assays quantifying the effects of AIT-induced IgE-blocking antibodies are advantageous. A cell-free enzyme-linked immunosorbent facilitated antigen binding (ELIFAB) assay of JC pollen was established. Methods: Serum IgE–allergen complexes were captured by immobilized recombinant CD23, and allergen–IgE–CD23 complexes were detected by a biotin-conjugated anti-human IgE antibody. Sera from JC pollen-allergic subjects without or with subcutaneous immunotherapy (SCIT) with JC pollen extract were used (n = 11/group). Results: Optimal assay conditions were established at 20 μg/mL CD23 and 0.3 μg/mL JC pollen extract, and the dependency on CD23 and IgE was verified. The data show that the JC pollen ELIFAB assay is fit for purpose and demonstrates that the IgE-blocking activity is significantly increased in the JC pollen SCIT group compared with the non-treated group. Conclusion: The JC pollen ELIFAB assay represents a simple, cell-free biomarker assay for monitoring the development of IgE-blocking antibody activity during JC pollen AIT. Keywords: Allergy immunotherapy, Allergic rhinitis, IgE-facilitated allergen presentation, Japanese cedar pollen, Subcutaneous immunotherapy

Japanese cedar pollen (JCP) and house dust mite (HDM) are two major allergens that cause allergic rhinitis (AR) in Japan and the prevalence of AR is increasing. Pharmacothearpy is a commonly used treatment, but the level of patient satisfaction is very low. Allergen immunotherapy (AIT) is the only therapeutic modality that provides not only symptom relief but also quality of life improvement that leads to a high rate of satisfaction. In particular, sublingual immunotherapy (SLIT) is a safe and effective treatment for AR. Here we introduce a large-scale double-blind, placebo-controlled trial of SLIT in Japanese patients using JCP droplets or HDM tablets conducted in Japan. The immediate future of SLIT in Japan is also discussed. Keywords: Allergen immunothearpy, Allergic rhinitis, HDM allergen, Japanese cedar pollinosis, Sublingual immunotherapy

Background: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. Methods: Japanese patients aged 5–65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). Results: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. Conclusions: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU. Keywords: Allergen immunotherapy, Allergic bronchial asthma, Allergic rhinitis, Clinical trial, House dust mite

The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)–based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy.

Background: Complementary and alternative medicine (CAM) is extensively used in patients with allergic diseases worldwide. The purpose of this study was to investigate the actual situation of CAM practice in the treatment of allergic rhinitis. Methods: We distributed questionnaires to otolaryngologists at 114 facilities in Japan. The subjects who participated in this study included children

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Hypereosinophilic syndrome (HES) is a systemic disease characterized by an increased peripheral blood eosinophil count accompanied by systemic organ dysfunction. HES is classified into idiopathic HES, primary (neoplastic) HES (HESN), and secondary (reactive) HES (HESR). In this case report, a patient who developed peripheral blood eosinophilia and granulation tissue in the pharynx and paranasal sinus, which was initially diagnosed as chronic eosinophilic leukemia (CEL), categorized as HESN, but was eventually identified after the patient had died as natural killer/T-cell (NK/T) lymphoma, nasal type (ENKL), categorized as HESR, is presented. ENKL-induced HES is very rare but must be considered.

Background: In the 1990s, the Japanese Society of Allergology (JSA) standardized Japanese cedar pollen allergen vaccines. In the present study, the task force for house dust mite (HDM) allergen standardization of the Committee for Allergens and Immunotherapy of JSA reports the standardization of HDM allergen vaccines in Japan. Methods: In vivo allergenic potency was determined by intradermal testing of 51 Japanese adults with positive serum specific IgE to HDM allergens. In vitro total IgE binding potency was analyzed by competition ELISA using a pooled serum, with sera obtained from 10 allergic patients. The amounts of HDM group 1 (Der 1) and group 2 major allergens in eight HDM allergen extracts were measured by sandwich ELISAs. Correlation between the in vitro total IgE binding potency and major allergen levels was analyzed. Results: We selected a JSA reference HDM extract and determined its in vivo allergenic potency. The in vitro total IgE binding potency significantly correlated with Der 1 content, group 2 allergen content, and their combined amount, indicating that measurement of major allergen contents can be used as a surrogate in vitro assay. Conclusions: The task force determined the in vivo allergenic potency (100,000 JAU/ml) and Der 1 content (38.5 μg/ml) of the JSA reference HDM extract, selected the measurement of Der 1 content as the surrogate in vitro assay, and decided that manufacturers can label a HDM allergen extract as having a titer of 100,000 JAU/ml if it contains 22.2–66.7 μg/ml of Der 1.

Background:: Chronic rhinosinusitis (CRS), which is clinically classified into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), shows considerable geographic differences and heterogeneity. Eosinophilic (E) CRS with nasal polyps (ECRSwNP) has a higher degree of disease severity and higher frequency of comorbid asthma. Epidemiologic studies in different ethnic populations have improved understanding of the pathophysiology of the disease. Here we report the clinical characteristics of Japanese patients with medically refractory CRS undergoing endoscopic sinus surgery (ESS). Methods:: We recruited a total of 210 CRS patients and assessed them by nasal endoscopy, the Lund-Mackay score using computed tomography (CT), peripheral eosinophilia and smoking status. We also examined the comorbidity of asthma, effects of age and lung functions in the patients. Results:: In this study, 13% of CRSwNP patients and 20% of CRSwNP patients with peripheral blood eosinophilia exhibited obstructive lung dysfunction (FEV1/FVC

Abstract.: The aim of the current study was to demonstrate highly specific and direct binding activity of tritium ([3H])-labeled imidafenacin for labeling muscarinic receptors in human bladder and parotid gland. Specific binding of [3H]imidafenacin in human tissues was saturable, reversible, and of high affinity. The Kd value for specific [3H]imidafenacin binding in the human bladder was approximately 3 times higher than that in the parotid gland. Unlabeled imidafenacin as well as the clinically used antimuscarinic agents, oxybutynin, tolterodine, and solifenacin, competed with [3H]imidafenacin for binding sites in the human bladder and parotid gland in a concentration-dependent manner, which indicated pharmacological specificity of [3H]imidafenacin binding sites. The Ki for imidafenacin in the human bladder approximately corresponded to pharmacological potency for the competitive blockade of carbachol-induced contractions of bladder, indicating a close correlation between binding affinity of imidafenacin to bladder muscarinic receptors and its pharmacological effects in the bladder. In conclusion, the current study is the first to provide direct evidence to demonstrate that imidafenacin bound muscarinic receptors in the human bladder, supporting its clinical relevance as a therapeutic agent for overactive bladder. [3H]Imidafenacin may also be a useful radioligand for labeling the M3 subtype of muscarinic receptors with higher selectivity than other radioligands. Keywords:: overactive bladder, [3H]imidafenacin, human bladder, parotid gland, muscarinic receptor

Background: In Japan, oral antihistamines are frequently used as the initial treatment for seasonal allergic rhinitis (SAR), and intranasal steroids are added when nasal symptoms worsen. This study aimed to evaluate whether starting treatment with fluticasone propionate nasal spray (FP) from the beginning of pollinosis symptoms and adding fexofenadine hydrochloride tablet (FEX) when SAR is aggravated could achieve improved amelioration of nasal symptoms throughout the pollen season in comparison with a treatment that involves starting with FEX and later adding FP. Methods: In this pragmatic, randomized, open-label, parallel-group trial, 51 Japanese cedar pollinosis patients (age, 16–85 years) were randomly divided and administered FP 100 mcg twice daily as an initial drug with FEX 60 mg twice daily as an additional drug and the same treatment in the reverse order. Nasal symptoms were evaluated in a daily dairy using a 4-point scale. The primary outcome was area under curve of the line representing the daily total nasal symptom score in the pollen season on a graph. Results: Initial treatment with FP was significantly (P=0.0015) more effective than initial treatment with FEX in improving the primary outcome. The average daily total nasal symptom score in the initial treatment with FP group was better than that in the initial treatment with FEX group throughout the pollen season. Conclusions: Initiating treatment with FP and adding FEX might lead to improved outcomes for nasal symptoms in comparison with the same drugs administered in the reverse order.

Background: The relationship between chronic rhinosinusitis (CRS) and asthma has been known for a long time. However, no large studies on the relationship between CRS and lower airway diseases have been reported to date in Japan. Additionally, eosinophilic chronic rhinosinusitis (ECRS) in Japan is considered to be a subgroup of CRS with nasal polyps (CRSwNP) characterized by eosinophil-dominant inflammation. However, the diagnostic criteria of ECRS have not been established. Methods: To investigate clinical and epidemiological features of patients with CRS from the aspect of their associations with lower airway diseases, 553 patients with CRS who visited one of six local university hospitals were examined and interviewed. Local eosinophilic infiltration was evaluated pathologically by exmining NPs. Results: The prevalences of olfactory dysfunction (OD) in the patients with nasal polyps (NPs) and those without NPs were 57.0% and 13.7%, respectively (p < 0.0001). The prevalence of asthma in all patients was 23.1%. Furthermore, the prevalences of NPs and OD in the patients with asthma and those without asthma were 81.0% and 50.1% (p < 0.0001) and 64.2% and 35.7% (p < 0.0001), respectively. 97.4% of the patients with asthma had >15% mucosal eosinophils, and 87.9% of the patients without asthma had

ABSTRACT: Background: Transforming growth factor-p (TGF-β) levels are elevated in the nasal mucosa in allergic rhinitis. However, because TGF-β is secreted extracellulary in latent complexes, it remains unclear whether the local TGF-β expression actually drives active signaling and affects the pathophysiology of allergic rhinitis. The objective of this study is to investigate whether TGF-β signaling is activated in allergic rhinitis and plays a role in the pathophysiology of allergic rhinitis. Methods: An ovabumin (OVA)-sensitized and -nasally challenged mouse model of allergic rhinitis was established and phosphorylation of Smad2 in the nasal mucosa was examined by immunohistochemistry. In addition, the effects of the pharmacological inhibition of endogenous TGF-β signaling on the allergic rhinitis model were histologically examined. Furthermore, phosphorylation of Smad2 in the nasal mucosa samples obtained from patients with allergic rhinitis was also evaluated. Results: In the mouse model of allergic rhinitis, OVA challenge induced phosphorylation of Smad2 predominantly in epithelial cells in the nasal mucosa. In addition, the administration of an inhibitor of TGF-β type I receptor kinase activity during OVA challenge suppressed goblet cell hyperplasia in the nasal mucosa. Furthermore, phosphorylated Smad2 expression increased in nasal epithelial cells in patients with allergic rhinitis. Conclusions: These results suggest that TGF-β signaling is activated in epithelial cells in the nasal mucosa in allergic rhinitis and may contribute to the development of goblet cell hyperplasia. KEY WORDS: allergic rhinitis, epithelial cells, Smad, TGF-p

Background: Allergen specific immunotherapy is highly effective, but adverse events may occur during treatment. Peptide-based immunotherapy has been proposed as one of new strategies for reduction of allergic adverse reactions. We examined the possibility of candidate peptides for the development of peptide-based immunotherapy for Japanese cedar pollinosis. Methods: Twelve Cry j 1-specific T-cell lines were established from peripheral blood mononuclear cells (PBMC) of 12 patients with Japanese cedar pollinosis. Using these T-cell lines, 37 Cry j 1-derived overlapping peptides were assessed for their proliferative responses and cytokine production. Results: Four peptides corresponding to the Cry j 1 sequence were able to induce proliferative responses to more than one T-cell line: p61-80 (3/12; 25.0%); p115–132 (2/12; 16.6%); p206–225 (4/12; 33.3%); and p337–353 (5/12; 41.7%). Furthermore, T-cell lines generated from 11 of 12 donors (91.7%) responded to at least one of these four peptides. On the other hand, the pattern of cytokine production from Cry j 1-specific T-cell lines varied. Moreover, cytokine production patterns by stimulation with Cry j 1 peptide did not reflect those by stimulation with Cry j 1 protein. Conclusions: Our results suggest four Cry j 1-derived peptides (p61–80, p115–132, p206–225 and p337–353) may be considered to be the immunodominant T-cell epitopes of the Cry j 1 molecule, and can be useful for the design of peptide-based immunotherapy for the management of Japanese cedar pollinosis.

Background: Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollen is a substantial problem in Japan. Sublingual immuno-therapy (SLIT) is safer than conventional antigen-specific immunotherapy, the only treatment modality by which complete cure of the disease can be expected. We investigated the safety and efficacy of SLIT in the treatment of cedar pollinosis patients compared to placebo. Methods: A randomized, placebo-controlled, double-blind study was conducted in 61 cedar pollinosis patients. Increasing doses of standardized Japanese cedar extract or placebo were administered sublingually in intervals ranging from daily to once a week after six weeks. The primary efficacy variable was the mean of the daily total symptom scores (TSS) during the pollen dispersing period. Secondary efficacy variables included the QOL scores and related variables. Results: Primary efficacy variable scores were significantly lower for some days in the SLIT group than in the placebo group (P < .01 or P < .05). Secondary efficacy for the QOL score in SLIT group was almost of half of placebo group. There was no significant difference in the overall incidence of side effects between the SLIT group and the placebo group. Conclusions: SLIT was effective and safe in the treatment of cedar pollinosis.

Background: Although prescribed drugs directly affect patient outcome, the variation in physicians' attitudes towards drug therapy for cedar pollinosis has not been quantitatively assessed. This research investigated the prescription patterns of drugs for cedar pollinosis by ear, nose, and throat specialists (ENTs), general physicians (GPs) and internal medicine doctors (IMs) in Yamanashi Prefecture, Japan. Methods: A cross-sectional study was conducted by mailing questionnaires to 532 physicians in autumn 2006. The main part of the questionnaire constituted clinical vignettes of pollinosis cases with nasal and ocular symptoms ranging from mild to severe. We requested that the physicians fill out prescription medications they considered appropriate for each vignette. Results: Responses from 172 physicians (32%) for six clinical vignettes were analyzed. The number of drugs prescribed by ENTs was significantly higher than that by GPs and IMs for vignettes representing moderate to severe cases (p < 0.004). The percentage of physicians who said they would prescribe nasal corticosteroid and eye drops was higher in the ENT group compared to the other two groups in these vignettes. In terms of second-generation antihistamines, no differences were observed between the three groups for all vignettes. Conclusions: Our investigation suggested that, compared to ENTs, GPs and IMs have a lower tendency to concomitantly prescribe drugs for localized treatment such as nasal corticosteroids and eye drops with oral medication. There may be differences in prescription patterns of drugs for pollinosis between ENTs and non-specialist physicians.

Hyalinizing clear cell carcinoma (HCCC), so-called clear cell carcinoma, not otherwise specified (CCC (NOS)), of the salivary glands is a rare and low-grade malignant tumor. We report a case of HCCC so-called CCC (NOS) (referred to as HCCC) of the minor salivary gland of the buccal mucosa. A 52-year-old woman had presented with a gradually growing and indolent mass in the right buccal mucosa for about two years. The first biopsy histopathologically suggested the possibility of malignancy derived from the minor salivary glands. A month later, she visited our hospital. The tumor measured approximately 1.5 cm in diameter and was elastic hard, smooth, and well movable. Image examinations demonstrated internal homogeneity of the lesion, which had a smooth margin, in the right buccal mucosa. Complete tumor resection followed by covering with a polyglycolic acid sheet and fibrin glue spray was performed without surgical flap reconstruction. Histopathological findings revealed proliferating tumor cells with clear cytoplasm surrounded by hyalinizing stroma in the submucosal minor salivary glands. Immunohistochemical stains revealed these tumor cells to be positive for epithelial cell markers but negative for myoepithelial ones. These findings confirmed the diagnosis of HCCC. Good wound healing and no evidence of local recurrence and metastasis have been shown since surgery.

We encountered a patient with primary cervical leiomyoma with remarkable calcification and ossification. A 68-year-old man presenting with induration and swelling of the left submandibular region was found to have nodular lesions with calcifications in the left submandibular region and the upper mediastinum on CT. Fine needle aspiration biopsies (FNAB) of the left submandibular lesion revealed no malignancy. Resection was performed for definitive diagnosis and treatment. The resected specimen contained a solid tumor, which was markedly calcified and ossified on the cut surface. Histopathological examination showed proliferating spindle cells in a tangled and crossed arrangement. Immunohistochemically, the spindle cells were stained intensely with α-SMA and h-caldesmon, consistent with smooth muscle cells. These findings led to a definitive diagnosis of leiomyoma with calcification and ossification. This is extremely rare and the preoperative differentiation from other tumors of the head and neck was very difficult. By resection of the submandibular tumor, both definitive diagnosis of leiomyoma by histopathological and immunohistochemical analyses and treatment could be carried out. However, as the tumor in the upper mediastinum was most likely to be leiomyoma with calcification, he did not wish to undergo its biopsy and resection immediately. We have continued the follow-up.

Eosinophils and neuropeptides are thought to play effector roles in allergic diseases, such as rhinitis; however, little is known about the biological effects of neuromediators, especially vasoactive intestinal peptide (VIP), on eosinophil functional responses. In the present study, it is shown that VIP induces eosinophil chemotaxis and eosinophil-derived neurotoxin (EDN) release in potency comparable with that induced by platelet activator factor, and in a novel synergistic manner with recombinant human interleukin-5. Contrary to chemotaxis, EDN release was sensitive to staurosporine, the protein kinase C inhibitor, as well as intracellular calcium chelation. However, eosinophil treatment with inhibitors of tyrosine kinases (herbimycin A) and phosphatases (pervanadate) resulted in a dose-dependent potentiation and blockage of VIP-induced eosinophil chemotaxis, respectively. Treatment of eosinophils with VIP receptor antagonist did not modify VIP-induced chemotaxis or EDN release. Furthermore, exploration of vasoactive intestinal peptide receptor I expression was lacking in human eosinophils, but not lymphocytes. These results demonstrate two different mechanisms in triggering eosinophil activation of functional responses by VIP, a calcium-dependent degranulation and a calcium-independent chemotaxis, and elaborate on a novel cytokine–neuropeptide interaction in eosinophilic inflammation.

The present study was performed in order to investigate the mechanism(s) involved in eotaxin-induced normal human eosinophil chemotaxis using a 48-well micro-chemotaxis chamber assay. Eotaxin, at a wide range of doses, induced eosinophil chemotaxis with optimal activity at 100 ng/mL. To elucidate the role of Ca2+ as a second messenger, eosinophils were depleted of intracellular Ca2+ which, per se, did not modify eosinophil chemotaxis. To gain insight of the possible intracellular signal transduction, we blocked pertussis toxin (PTX)-sensitive Gj proteins as well as several protein kinases. It was found that the inhibition of tyrosine kinase with herbimycin A and the inhibition of mitogen-activated protein kinase (MAPK) with MEK-1 inhibitor (PD98059) significantly blocked chemotaxis; however, inhibition of protein kinase C with staurosporine, protein kinase A with H-89 and Gi proteins with PTX did not affect chemotaxis. These results suggest a signal transduction pathway(s) involving Ca2+-independent tyrosine kinase and MAPK activities.

The occupational uses of latex gloves may be associated with allergic rhinitis. Hypersensitivity to latex has been shown to be IgE-mediated. However, late nasal responses to latex have not been reported. The present report describes a clinical and immunological study of a dental nurse with work-related rhinitis induced by the use of latex gloves. To examine whether late nasal symptoms were associated with infiltration of T cells and eosinophils and also with preferential expression of T helper 2 (Th2) cell type cytokine mRNA, nasal biopsies were performed before and 24 h after latex provocation and were processed for immunohistology and in situ hybridization. Latex induced early and late nasal responses. After latex provocation, the numbers of T cells and eosinophils were markedly increased compared with number on the control day. In situ hybridization confirmed Th2 type cytokine mRNA expression at 24 h after latex provocation. These results suggest that latex provokes IgE-mediated early and late nasal responses and that late nasal symptoms are associated with an infiltration of T cells and eosinohils and the production of Th2 type cytokines.

Aspirin-induced asthma is often accompanied by nasal polyps, in which tissue eosinophils are abundant and activated. However, the mechanism of eosinophil infiltration remains unknown. We encountered two aspirin-induced asthma patients with nasal polyps and investigated eosinophil infiltration into nasal polyp tissue. Eosinophil chemotactic activity of extracts from the nasal polyp was elevated and could be inhibited by 40% with anti-interleukin (IL)-5 antibody. Interleukin-5 was detectable in the extract. The chemotactic activity of peripheral blood eosinophils to recombinant human (rh)IL-5 was increased compared with normal volunteers. Messenger RNA expression for IL-5 in CD3+ lymphocytes for polyp tissue was detected using the reverse transcription-polymerase chain reaction. These results suggest that IL-5 from local T lymphocytes may be one of the candidates for recruitment of eosinophils into nasal polyps in aspirin- induced asthma.