ニッケルアレルギー惹起相におけるセマフォリン７Aの効果

Background: Metal allergy is caused by many factors, including cells, cytokines, chemokines, or the environment. Recent studies suggested semaphorin7A (Sema7A), expressed on activated T cells, is crucial to produce inflammation through α1β1 integrin on monocytes and macrophages. However, the role of Sema7A on keratinocytes in metal allergy is still unclear. In this study, we focused on keratinocytes since they are known as an important player for skin immunity, and analyzed the effect of Sema7A expressed on keratinocytes in the development of metal allergy. Materials and Methods: Mouse keratinocyte line PAM2.12 cells were treated with NiCl2 to analyze the expression of Sema7A. Ni allergy was induced in female C57BL/6J mice (6-8 weeks old) with or without Sema7A suppression to confirm if Sema7A is necessary to produce allergic reactions to NiCl2. Results: NiCl2 enhanced the expression of Sema7A in a dose and time-dependent manner after 72 hours of stimulation. PAM 2.12 produced TNF-α in response to NiCl2, and this secretion was reduced by Sema7A inhibition. In a mouse model, ear thickness, at 48 hours after NiCl2 injection, was significantly decreased by Sema7A siRNA administration. Conclusions: Sema7A is essential to produce an allergic reaction to NiCl2, especially during the effector phase. Since the interaction between Sema7A and α1β1 integrin enhances inflammation in many skin diseases, this interaction may also have possibilities to be a therapeutic target for metal allergy

Semaphorin 3A : A potential target for prevention and treatment of nickel allergy

Metal allergy is one of the typical immune disorders encountered during the application of dental/medical materials and has a highly complex pathogenic mechanism. Semaphorin 3A (Sema3A), a member of the semaphorin family, is reported to be involved in various immune disorders. However, its role in metal allergy has not been clarified yet. Herein, we show that Sema3A expression was upregulated in nickel (Ni) allergy-induced mouse ear tissue and in NiCl2-stimulated mouse keratinocytes. Moreover, Sema3A regulated tumor necrosis factor-alpha production and mitogen-activated protein kinase activation in keratinocytes. The specific deletion of Sema3A in keratinocytes did not affect immune cell infiltration but reduced edema and ear swelling; it also impeded Th1 responses to cause a slight alleviation in Ni allergy in mice. Our results demonstrate that Sema3A promotes the development of metal allergy and should be explored as a potential target for the prevention and treatment of metal allergy

Neonatal Lethality in Knockout Mice Expressing the Kinase-Dead Form of the Gefitinib Target GAK Is Caused by Pulmonary Dysfunction

Gefitinib (Iressa) is an inhibitor of the epidermal growth factor receptor (EGFR) that has shown promising activity in the treatment of patients with non-small cell lung cancer (NSCLC). However, adverse side effects of gefitinib treatment, such as respiratory dysfunction, have limited the therapeutic benefit of this targeting strategy. The present results show that this adverse effect can be attributed to the inhibition of the novel gefitinib target GAK (Cyclin G-associated kinase), which is as potently inhibited by the drug as the tyrosine kinase activity of EGFR. Knockout mice expressing the kinase-dead form of GAK (GAK-kd) died within 30 min after birth primarily due to respiratory dysfunction. Immunohistochemical analysis revealed that surfactant protein A (SP-A) was abundant within alveolar spaces in GAK-kd+/+ mice but not in GAK-kd-/- pups. E-cadherin and phosphorylated EGFR signals were also abnormal, suggesting the presence of flat alveolar cells with thin junctions. These results suggest that inhibition of GAK by gefitinib may cause pulmonary alveolar dysfunction, and the present study may help prevent side effects associated with gefitinib therapy in NSCLC patients

Hardness, Cohesiveness, and Adhesiveness of Oral Moisturizers and Denture Adhesives : Selection Criteria for Denture Wearers

The mechanical properties of seven denture adhesives and eight oral moisturizers, all of which are commercially available, were evaluated using a texture profile analysis. A new assessment chart is proposed for the selection criteria of denture adhesive and oral moisturizers using a radar chart with three axes: hardness, cohesiveness, and adhesiveness

Present Status of Blood Pressure Control in a Group of Hypertensive Patients Followed-up in a Cardiovascular Outpatient Clinic

Information on blood pressure control in treated hypertensive patients attending hospital clinics is very scarce in Japan. We investigated the present status of blood pressure control in a large group of 946 consecutive hypertensive patients attending the cardiovascular out-patient clinic of our hospital during a period of a month between 1 April and 30 April 2001. The average blood pressure during the patient\u27s past three visits to the out-patient clinic was 138/83 mm Hg. Patients were divided into 5 age groups. Diastolic blood pressure significantly decreased with age and pulse pressure significantly increased with age, while systolic blood pressure did not differ significantly among the 5 age groups. With regard to blood pressure control, 50% of these patients achieved blood pressure levels less than 140/90 mm Hg, and only 23% achieved blood pressure levels less than 130/85 mm Hg. The achievement rate of blood pressure less than 140/90 mm Hg was the lowest in the group of patients aged less than 50 years among the 5 age groups. The achievement rates of diastolic blood pressure less than 90 mm Hg, 85 mm Hg, and 80 mm Hg were also the lowest in the group of patients aged less than 50 years. The achievement rate of systolic blood pressure less than 140 mm Hg was the lowest in the group of patients aged 80 years or more, although this was not significant. Calcium antagonists were the most prescribed drugs irrespective of age. The prescription rate of calcium antagonists increased with age, while that of β blockers tended to decrease with age. It could be concluded that more efforts should be made to control diastolic blood pressure especially in patients aged less than 50 years as well as to control systolic blood pressure in elderly patients

金属アレルギーはTSLP-TSLPRシグナルを介して口腔扁平苔癬の発症に関与する

Metal allergy is a T-cell-mediated delayed type of hypersensitive reaction. The pathogenetic mechanisms underlying the allergy are unclear, although the condition has been reported to be related to oral lichen planus (OLP), despite an absence of immunological studies to support this relationship. In this study, histopathological samples of OLP patients were examined to compare the metal allergy-positive and -negative groups, with a focus on the network of epidermal keratinocytes and T cells induced by thymic stromal lymphopoietin (TSLP) and its receptor, TSLPR. Infiltration of T cells into the epithelium was revealed to be higher in the OLP lesions of metal allergy-positive patients than in those of metal allergy-negative patients. Moreover, TSLP-TSLPR signaling and TNF-α production were higher in the epithelial tissue samples of the metal allergy-positive patients than in the metal allergy-negative patients. Metal allergy is associated with both increased expressions of TSLP in keratinocytes and increased TNF-α levels in the epithelium. We propose that this would promote the accumulation of T cells at the lesion site, contributing to the formation of the disease. These results suggest that metal allergy may be an aggravating factor in the pathogenesis of OLP

樹状細胞はニッケルアレルギーの発症時にニッケルイオンを抗原として直接認識する

Metal hypersensitivity, a disorder of the immune system, typically manifests as contact hypersensitivity to metals during daily contact. The molecular mechanism whereby metals enter the body and cause allergic disorders remains elusive. It is thought that eluted metal ions are captured by dendritic cells (DCs) and transferred to the draining lymph nodes to activate T cells. Here, for the first time, we used a metal indicator Newport Green to locate the most common allergenic metal, nickel (Ni) ions, captured by DCs and transferred to lymph nodes. Capturing Ni ions did not affect the activity of DCs. Ni ions entered DCs and showed positive staining in keratinocytes. A time varied quantitative analysis demonstrated that at 1 h, a small amount of Ni ions was observed in the epidermal sheet. After 6 h, the number of Ni ions that entered the epidermal sheet reached a peak and remained constant for a few days and were gradually emitted 48 h later. In the cervical lymph nodes of mice, accumulation of Ni ions reached a peak within 24 h and then gradually decreased. The findings of this study will contribute to the development of effective diagnoses and treatment methods for patients allergic to Ni