Hideyuki Kawauchi

Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study.

Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS.

Overexpression of IL-15 In Vivo Enhances Tc1 Response, Which Inhibits Allergic Inflammation in a Murine Model of Asthma

IL-15, a pleiotropic cytokine, is involved in the inflammatory responses in various infectious and autoimmune diseases. We have recently constructed IL-15-transgenic (Tg) mice, which have an increased number of memory-type CD8+ T cells in the peripheral lymphoid tissues. In the present study, we found that eosinophilia and Th2-type cytokine production in the airway were severely attenuated in OVA-sensitized IL-15-Tg mice following OVA inhalation. IL-15-Tg mice preferentially developed Tc1 responses mediated by CD8+ T cells after OVA sensitization, and in vivo depletion of CD8+ T cells by anti-CD8 mAb aggravated the allergic airway inflammation in IL-15-Tg mice following OVA inhalation. Adoptive transfer of CD8+ T cells from OVA-sensitized IL-15-Tg mice into normal mice before OVA sensitization suppressed Th2 response to OVA in the normal mice. These results suggest that overexpression of IL-15 in vivo suppresses Th2-mediated-allergic airway response via induction of CD8+ T cell-mediated Tc1 response.

APOPTOSIS DURING INNER EAR DEVELOPMENT IN HUMAN AND MOUSE EMBRYOS : AN ANALYSIS BY COMPUTER-ASSISTED THREE-DIMENSIONAL RECONSTRUCTION

 Apoptosis in the developing inner ear tissue of human (Carnegie stage 14 to 21, approximately 5 to 8 weeks of gestation) and mouse (10.5 to 14 days of gestation) embryos was systematically analyzed by a computer-assisted three-dimensional reconstruction of the serial histological sections and by the TUNEL method. Morphogenetic events such as folding between the utricular portion and endolymphatic duct, constriction of the junction of the saccule with the cochlea and folding of the vestibular portion to form the semicircular ducts were accompanied by a localized distribution of apoptosis. The apoptosis was also related to the innervation of the cochlear and vestibular epithelia from the sensory ganglion of the eighth cranial nerve and the differentiation of the otic epithelia into the sensory epithelia. These results suggest that apoptosis plays an important role in the development of the inner ear.

Effects of secretory leucocyte protease inhibitor on the production of the anti-inflammatory cytokines, IL-10 and transforming growth factor-beta (TGF-β), by lipopolysaccharide-stimulated macrophages

We studied the effects of secretory leucocyte protease inhibitor (SLPI) on the production of the anti‐inflammatory cytokines, IL‐10 and TGF‐β, by lipopolysaccharide (LPS)‐stimulated macrophages, using half‐sized SLPI (1/2 SLPI) containing the C‐terminal domain (Arg58‐Ala107). ELISA testing of macrophage culture fluids showed a temporary production of IL‐10 by the macrophages in the early phase (24 h) after LPS stimulation at low (1 ng/ml) or high (10 μg/ml) concentrations. On the other hand, TGF‐β production was initiated after day 3 and progressively increased. 1/2 SLPI significantly increased IL‐10 and TGF‐β production by macrophages in response to a low dose as well as a high dose of LPS. Reverse transcription‐polymerase chain reaction analysis showed that 1/2 SLPI caused a significant increase in the expression of both IL‐10 and TGF‐β mRNAs by LPS‐stimulated macrophages. Thus, although the profile of macrophage TGF‐β production by LPS‐stimulated macrophages is markedly different from that of their IL‐10 production, SLPI causes an up‐regulation of the production of these anti‐inflammatory cytokines by LPS‐stimulated macrophages.

Examination, diagnosis and classification for Japanese allergic rhinitis: Japanese guideline

Many countries throughout the world have experienced an increase in the prevalence of allergic rhinitis (AR), which has come to be a major cause of morbidity in developed countries. The pathology underlying AR is regarded as IgE-mediated type I allergy characterized by mucosal inflammation that occurs in response to allergen exposure. In Japan, AR caused by Japanese cedar pollen, the most common allergic disease, has become a salient public health challenge. Almost all primary care physicians and otorhinolaryngologists have been consulted by AR patients between February and April. Although most such patients have received treatment, numerous patients with AR have not received proper examinations for AR. Clinical guidelines are systematically developed statements that are designed to help practitioners make decisions about appropriate and effective health care. Guidelines in many countries including Japan have been published for AR. Unfortunately, those guidelines have remained untested. Moreover, they might be difficult for non-specialists to use. In this review, we specifically examine the present standard examination for diagnosis of AR and optimal classification for AR in Japan. We hope that this review would be used not only for the support of daily practice but also for selection of AR patients for clinical trials.

Canalith Repositioning Procedures among 965 Patients with Benign Paroxysmal Positional Vertigo

Background: Canalith repositioning procedure (CRP) has increasingly been utilized for the last 15 years for the treatment of benign paroxysmal positional vertigo (BPPV). We assess the short- and long-term efficacy of CRP on the treatment of patients with BPPV. Methods: Nine hundred sixty-five patients (481 men and 484 women, from 18 to 87 years of age) were enrolled in this prospective study during 1995–2010. Inclusion criteria were a patient history compatible with BPPV and a positive provocative maneuver (either Dix-Hallpike or Roll test). Reported duration of symptoms at the time of their first examination varied from 1 day to 18 months. Variants of the Epley and Barbeque maneuver were used for posterior and anterior canal involvement, and horizontal canal involvement, respectively. Short-term follow-up was obtained 48 h and 7 days after initial treatment, whereas long-term follow-up was obtained at repeated 6-month intervals. Results: Symptoms subsided immediately in 819 patients (85%) by the first CRP. Only 19 patients (2%) required CRP more than 3 times. Patients’ mean follow-up was 74 months; symptom recurrence was noted in 139 patients. A statistically significantly higher recurrence rate was noted in elderly people or those with head trauma or a history of vestibular neuropathy (p < 0.001). Conclusions: This study provides class IV evidence that CRP remains an efficient and long-lasting noninvasive treatment for BPPV, especially for younger patients without a history of head trauma or vestibular neuropathy. Elderly people have a significantly higher recurrence rate requiring additional education to minimize potential morbidity of their falls.

Dichotomous effect of a traditional Japanese medicine, Bu-zhong-yi-qi-tang on allergic asthma in mice

To determine the potentiality of prophylactic and/or therapeutic approaches using a traditional herbal medicine, Bu-zhong-yi-qi-tang (Japanese name: Hochu-ekki-to, HOT), for the control of allergic disease, we examined the effects of oral administration of HOT on a murine model of asthma allergic responses. When oral administration of HOT was begun at the induction phase immediately after OVA sensitization, eosinophilia and Th2-type cytokine production in the airway were reduced in OVA-sensitized mice following OVA inhalation. The serum levels of OVA-specific immunoglobulin (Ig)E and IgG1 were significantly decreased, whereas the level of OVA-specific IgG2a was increased. Interleukin (IL)-4 production by spleen T cells in response to OVA was significantly suppressed, while Interferon (IFN)-gamma production was increased in mice treated with HOT in the induction phase. On the other hand, HOT given in the eliciting phase induced a predominant Th2 response with increased IgE production in OVA-sensitized mice following OVA inhalation. These results suggest that the oral administration of HOT dichotomously modulates allergic inflammation in a murine model for asthma, thus offering a different approach for the treatment of allergic disorders.

Regulatory Role of Lymphoid Chemokine CCL19 and CCL21 in the Control of Allergic Rhinitis

The lymphoid chemokines CCL19 and CCL21 are known to be crucial both for lymphoid cell trafficking and for the structural organization of lymphoid tissues such as nasopharynx-associated lymphoid tissue (NALT). However, their role in allergic responses remains unclear, and so our current study aims to shed light on the role of CCL19/CCL21 in the development of allergic rhinitis. After nasal challenge with OVA, OVA-sensitized plt (paucity of lymph node T cells) mice, which are deficient in CCL19/CCL21, showed more severe allergic symptoms than did identically treated wild-type mice. OVA-specific IgE production, eosinophil infiltration, and Th2 responses were enhanced in the upper airway of plt mice. Moreover, in plt mice, the number of CD4+CD25+ regulatory T cells declined in the secondary lymphoid tissues, whereas the number of Th2-inducer-type CD8α−CD11b+ myeloid dendritic cells (m-DCs) increased in cervical lymph nodes and NALT. Nasal administration of the plasmid-encoding DNA of CCL19 resulted in the reduction of m-DCs in the secondary lymphoid tissues and the suppression of allergic responses in plt mice. These results suggest that CCL19/CCL21 act as regulatory chemokines for the control of airway allergic disease and so may offer a new strategy for the control of allergic disease.

Efficient induction of oral tolerance by fusing cholera toxin B subunit with allergen-specific T-cell epitopes accumulated in rice seed.

Cholera toxin B (CTB) subunit is an efficient mucosal carrier molecule for induction of oral tolerance to antigens and allergens. Here, T-cell epitopes of Cry j 1 and Cry j 2, major allergens in Japanese cedar pollen, were expressed in rice seed as a fusion protein with either CTB or rice glutelin as a control. Feeding mice with rice seed containing CTB-fused T-cell epitopes suppressed allergen-specific IgE responses and pollen-induced clinical symptoms at 50-fold lower doses of T-cell epitopes than required when using control seed. Our findings present a novel potential strategy for immunotherapy of type-I allergy.

The modulating effects of proinflammatory cytokines interferon‐gamma (IFN‐γ) and tumour necrosis factor‐alpha (TNF‐α), and immunoregulating cytokines IL‐10 and transforming growth factor‐beta (TGF‐β), on anti‐microbial activity of murine peritoneal macrophages against Mycobacterium avium‐intracellulare complex

We assessed the roles of proinflammatory cytokines IFN‐γ and TNF‐α, and immunoregulatory cytokines IL‐10 and TGF‐β in the modulation of the anti‐microbial activity of murine peritoneal macrophages against Mycobacterium avium‐intracellulare complex (MAIC). First, both IFN‐γ and TNF‐α significantly reduced the bacterial growth in macrophages, indicating that these cytokines participate in up‐regulation of macrophage anti‐MAIC function. Second, although MAIC‐infected macrophages produced substantial amounts of IL‐10 and TGF‐β, neutralization of endogenous IL‐10 and TGF‐β with anti‐IL‐10 and anti‐TGF‐β antibodies, respectively, did not affect the intracellular growth of MAIC in macrophages from mice with BcgS (MAIC‐susceptible) or Bcgr (MAIC‐resistant) genotype, regardless of the virulence of test MAIC strains. The same result was also obtained for macrophages stimulated with IFN‐γ or TNF‐α. Third, in MAIC‐infected mice, the growth of organisms at the sites of infection (lungs and spleens) was not affected by administration of anti‐IL‐10 or anti‐TGF‐β antibodies. These findings indicate that, in the case of mice, endogenous IL‐10 and TGF‐β are essentially ineffective in down‐regulating macrophage anti‐MAIC functions not only in vitro but also in vivo.