In addition to the studies of cellular and molecular events in the pathogenesis of systemic vasculitis, a genome analysis of mouse models may shed some light on the complex clinicopathological manifestations of systemic vasculitis. In the study of susceptibility loci to vasculitis in MRL mouse models, we learned that systemic vasculitis developed in a cumulative effect of multiple gene loci, each of which by itself did not have a significant effect to induce the related phenotype, thus indicating a polygenic system. The mice developed vasculitis in an additive manner of multiple genes with a hierarchical effect. Some of the susceptibility loci seemed to be common to those in other collagen diseases as well. Moreover, the loci controlling tissue specificity of vasculitis were present. One of the positional candidate genes for vasculitis showed an allelic polymorphism in the coding region, thus possibly causing a qualitative difference in its function. As a result, a particular combination of polygenes with such an allelic polymorphism may thus play a critical role in leading the cascade reaction to develop vasculitis, and also a regular variation of systemic vasculitis. This is designated as the polygene network in systemic vasculitis.

抄録全体を表示

Among small-vessel vasculitides, microscopic polyangiitis (MPA), Wegener's granulomatosis (WG), and allergic granulomatous angiitis (AGA) are known collectively as ANCA-associated vasculitis (AAV) because of the involvement of anti-neutrophil cytoplasmic antibodies (ANCA) as the common pathogenesis. Major target antigens of ANCA associated with vasculitis are myeloperoxidase (MPO) and proteinase 3 (PR3). MPO-ANCA is related to MPA and AGA, and PR3-ANCA is the marker antibody in WG. MPO-ANCA-associated vasculitis is more frequent in Japan, whereas PR3-ANCA-associated vasculitis is more common in Europe and USA. ANCA appears to induce vasculitis by directly activating neutrophils. Therefore, no immunoglobulins or complement components are detected in the vasculitis lesions; hence, AAV is called pauci-immune vasculitis (pauci = few/little). Untreated patients with severe AAV with multi-organ involvement have a poor prognosis, which is improved by combination therapy with cyclophosphamide and high-dose corticosteroid. Randomized controlled trials (RCT) regarding induction and maintenance of remission of AAV indicated that the rate of remission induction by the standard regimen is approximately 90% in 6 months, that maintenance of remission can be achieved with oral azathioprine as well as cyclophosphamide, and that methotrexate can be used only for non-renal mild AAV. As these data were obtained mostly in patients positive for PR3-ANCA, caution must be taken in applying these findings to Japanese patients, most of whom are positive for MPO-ANCA. A prospective study is now underway to clarify the effectiveness of the standard regimen in Japanese patients with MPO-ANCA-associated vasculitis. This article describes the diagnostic criteria and the recent evidence-based therapeutic strategy of AAV.

抄録全体を表示

Churg-Strauss syndrome (CSS) is characterized by the presence of asthma, eosinophilia, and small-vessel vasculitis with granuloma. It is a distinct entity, as determined from all classifications of systemic vasculitis. The poor prognostic factors in CSS are renal insufficiency, cardiomyopathy, severe gastrointestinal (GI) tract, and central nervous systems (CNS) involvement. The initial management of CSS should include a high dose of a corticosteroid: prednisone at 1 mg/kg/day or its equivalent for methylprednisolone with tapering over 6 months. In patients with severe or rapidly progressing CSS, the administration of methylprednisolone pulse at 1 g/body/day for 3 days is recommended. When corticosteroid therapy does not induce remission, or when patients have poor prognostic factors, immunosuppressive cytotoxic therapy is indicated. However, some patients with severe CSS often show resistance to conventional treatment. We think that IVIG therapy is a hopeful candidate for second-line treatment for CSS patients, particularly in the case of neuropathy and/or cardiomyopathy, which are resistant to conventional therapy. However, there is not much evidence supporting the effectiveness of IVIG in CSS, and the mechanisms underlying the action of IVIG remain unclear. Now we are performing clinical trials of IVIG therapy for CSS patients who are resistant to conventional treatment, through a nationwide double-blinded placebo-controlled study in Japan.

抄録全体を表示

Treatments of vasculitides have progressed markedly over the past few decades. The first attempts to obtain better-adapted therapeutic strategies evaluated the indications of conventional drugs, and their abilities prolong survival and reduce the number of relapses, while decreasing the severity and number of side effects. Many prospective clinical trials were organized by the French Vasculitis Study Group and the European Vasculitis Study group, and have contributed to optimizing targeted treatment strategies. Recent therapeutic strategies include immunomodulating methods, like plasma exchanges, or products, like intravenous immunoglobulins, or, more recently, new agents called biotherapies. Some of them have achieved promising positive effects, for example, anti-CD20 monoclonal antibodies, and are now being evaluated in prospective trials.

抄録全体を表示

The prevalence of allergic diseases has increased all over the world during the last two decades. Dietary change is considered to be one of the environmental factors that cause this increase and worsen allergic symptoms. If this is the case, an appropriate intake of foods or beverages with anti-allergic activities is expected to prevent the onset of allergic diseases and ameliorate allergic symptoms. Flavonoids, ubiquitously present in vegetables, fruits or teas possess anti-allergic activities. Flavonoids inhibit histamine release, synthesis of IL-4 and IL-13 and CD40 ligand expression by basophils. Analyses of structure-activity relationships of 45 flavones, flavonols and their related compounds showed that luteolin, ayanin, apigenin and fisetin were the strongest inhibitors of IL-4 production with an IC₅₀ value of 2-5 μM and determined a fundamental structure for the inhibitory activity. The inhibitory activity of flavonoids on IL-4 and CD40 ligand expression was possibly mediated through their inhibitory action on activation of nuclear factors of activated T cells and AP-1. Administration of flavonoids into atopic dermatitis-prone mice showed a preventative and ameliorative effect. Recent epidemiological studies reported that a low incidence of asthma was significantly observed in a population with a high intake of flavonoids. Thus, this evidence will be helpful for the development of low molecular compounds for allergic diseases and it is expected that a dietary menu including an appropriate intake of flavonoids may provide a form of complementary and alternative medicine and a preventative strategy for allergic diseases. Clinical studies to verify these points are now in progress.

抄録全体を表示

Background: A pollen exposure chamber (OHIO Chamber) was built in central Tokyo, Japan, in order to study seasonal allergic rhinitis (SAR). Since satisfactory outcomes were obtained from the controlled pollen exposure at the chamber, we conducted preliminary studies in volunteers with SAR.
Methods: Ten volunteers with SAR sensitive to Japanese cedar (JC) pollen were enrolled in this study. In order to investigate the intranasal and intraocular pollen number, volunteers were initially exposed to a low concentration of JC (2500 grains/m³) for at most 1 hour in this chamber. Before and after the exposure, nasal cavities and eyes were washed with 100ml and 25ml of saline, respectively. Nasal and eye washing solutions were collected and the number of JC pollen was counted.
After 3 hours the volunteers were subsequently exposed to a moderate concentration of JC (4500 grains/m3) for 2 hours. Subjective nasal and ocular symptoms were recorded and the amount of nasal secretion was measured during the allergen exposure periods.
Results: During the initial exposure, all volunteers except one stayed in the chamber for 1 hour without any nasal or ocular symptoms. The number of pollen in the nose and eyes was 249.2 ± 120.9 and 13.6 ± 13.6 grains, respectively.
During the subsequent 2-hour exposure to JC pollen, nasal and ocular symptoms developed gradually in a time dependent manner in all the volunteers except one.
Conclusions: This is the first clinical study using Japanese cedar pollen under well-controlled conditions in the OHIO chamber in which the induction of allergic symptoms was observed. The OHIO chamber will be useful for studying allergic rhinitis in Japan.

抄録全体を表示

Background: Fructooligosaccharides (FOS) in prebiotic foods can alter intestinal immune responses. The combination of probiotics with oligosaccharides has been reported to alter intestinal flora and suggested to be beneficial against food allergy in humans.
Methods: All male Nc/jic mice used in this 8-week study were 6 weeks of age and were allotted to the following three groups: (1) the nonsensitization group; (2) the ovalbumin (OVA) sensitization +5% fructose-containing control food administration group; and (3) the OVA sensitization +5% FOS-containing food administration group. Duodenal tissues were collected and then immunohistochemically stained with monoclonal antibodies to CCR4 and CCR5. The number of mast cells and the villus edema formation rate in the duodenum were determined by image analysis.
Results: The number of CCR4-positive cells increased significantly in Group 2 as compared with Group 1 and tended to decrease in Group 3 as compared with Group 2. Relatively few CCR5-positive cells were observed in the duodenum. FOS tended to reduce the number of CCR4-positive cells but significantly reduced the number of mast cells and the edema formation rate in the duodenum.
Conclusions: This study demonstrated a correlation between the number of CCR4-positive cells and villus edema formation rate. Therefore, FOS, which we inferred to show antiallergic activity for food allergy in this study and which has already been established to be safe for use as food in humans, can be considered to be potentially useful for the prevention of food allergy in pediatric patients with allergy.

抄録全体を表示

Background: Atopic dermatitis is a chronically relapsing inflammatory skin disease. Animal models induced by relevant allergens play a very important role in the elucidation of the disease. The patients with atopic dermatitis are highly sensitized with mite allergens such as Dermatophagoides farinae (Df). Therefore, in the present study, we tried to develop a novel model for atopic dermatitis by repeated application with Df extract ointment.
Methods: Df extract ointment was repeatedly applied to the back of NC/Nga mice together with barrier disruption. Atopic dermatitis-like skin lesions were evaluated by dermatitis scores, skin histology and immunological parameters. The effect of corticosteroid and calcineurin inhibitor was also examined.
Results: Repeated application of Df extract ointment caused rapid increase in dermatitis scores. Clinical (skin dryness, erythema, edema and erosion) and histological symptoms (dermal and epidermal thickening, hyperkeratosis, parakeratosis and inflammatory cell infiltration) in this model were very similar to those in human atopic dermatitis. Serum total and Df-specific IgE levels were elevated in this model compared with normal mice, and draining lymph node cells isolated from the mice that exhibited dermatitis produced significant amounts of interleukin-5, interleukin-13 and interferon-γ after re-stimulation with Df. Furthermore, current first-line drugs for the treatment of human atopic dermatitis, corticosteroid and tacrolimus ointments, were effective against the clinical and histological symptoms in this model.
Conclusions: These results suggest that the model we have established is useful for not only elucidating the pathogenesis of atopic dermatitis but also for evaluating therapeutic agents.

抄録全体を表示

Background: Phenytoin can induce diversified adverse reactions including generalized eruptions and the hypersensitivity syndrome. Delayed-type allergic mechanisms have been postulated to underlie these reactions. The tests most widely used to detect T-cell sensitization to drugs are the patch test and the lymphocyte transformation test (LTT), but their sensitivity is not sufficient. Simultaneous assessment of both the frequencies and the cytokine-producing phenotypes of allergen-specific T cells has become possible with the recently introduced carboxyfluorescein succinimidyl ester (CFSE) assay.
Methods: Seven patients who presented with phenytoin-induced maculopapular exanthema with and without fever were included in this study. Peripheral blood mononuclear cells (PBMCs) were labeled with CFSE and cultured with phenytoin for seven days. The cells were stained with anti-CD4 and cytokine-specific monoclonal antibodies (MoAbs), and analyzed with FACSCalibur.
Results: The phenytoin-specific proliferation of CD4⁺ cells in patients was significantly higher than in the four controls exposed to phenytoin, and in seven healthy children with no previous phenytoin intake. A significant difference in the percentages of CD4⁺ IFN-γ⁺ cells between patients and the seven healthy children was observed. The sensitivity and specificity of proliferation were 100% and 90.9%, and those of IFN-γ secretion were 71.4% and 100%, respectively.
Conclusions: Phenytoin-specific proliferation may be detected with greater sensitivity by the CFSE dilution assay than the conventional LTT. The assay revealed that both CD4⁺ and CD4^- T cells proliferated and produced IFN-γ and TNF-α after stimulation with phenytoin. The CFSE dilution assay might be useful for the diagnosis and understanding of drug hypersensitivity.

抄録全体を表示

Background: Respiratory syncytial virus (RSV) infection causes asthma-like symptoms in infants and young children. Although an increase in several mediators in the airway during RSV infection has been reported, the mechanisms involved in airway inflammation are not fully understood. The aim of this study was to investigate the immunological deviation associated with airway inflammation by measuring cytokine and chemokine levels in the airway during RSV infection.
Methods: One hundred and ten children under 3 years of age with respiratory symptoms were enrolled in this study from November 2004 through January 2005. Nasopharyngeal secretions (NPAs) were gently aspirated and analyzed with RSV antigen, thereafter the concentrations of IL-4, IL-10, IFN-γ, and RANTES were measured using an ELISA kit. We also investigated the prognosis of each child after 1 year by reference to clinical records or by interviews and re-evaluated the cytokine and chemokine levels.
Results: Of the subjects, 70 children were RSV positive and 40 were negative. Only 4 children were given a diagnosis of asthma by the pediatrician when NPAs were collected. The levels of IL-4, IL-10, and RANTES were significantly higher in the RSV-positive patients than RSV-negative patients with P values at 0.0362, 0.0007, and 0.0047, respectively. In contrast, there was no significant difference in the levels of IFN-γ. Furthermore, there was a significant positive correlation between IL-10 and RANTES.
Conclusions: The increased production of IL-4, IL-10, and RANTES in the airway may play an important role in the pathophysiological mechanisms of RSV infection.

抄録全体を表示

Background: Pulmonary dendritic cells (DCs) play critical roles in both allergy and in viral infection. Levels of cysteinyl leukotrienes (cysLTs) increase after allergen sensitization and viral infection and can modulate the migration and functions of DCs. The present study examines the effects of respiratory syncytial virus (RSV) infection on numbers of DCs and cysLT concentrations in lung tissues of mice sensitized with mite allergen.
Methods: We examined Control, Dermatophagoides farinae allergen sensitized (Df), RSV infected (RSV) and Df allergen sensitized and RSV infected (Df-RSV) Balb/c mice. We then determined the number of CD11c-positive DCs and the LT concentration in lung tissues of the mice and examined lung pathology and cytokine profiles in thoracic lymph nodes.
Results: Infection with RSV significantly enhanced allergic airway inflammation in Df mice with concomitant increases in Th1 and Th2 immunity. The number of DCs and the cysLT concentrations were significantly increased in the lungs of Df and RSV mice and more so in Df-RSV, than in Df mice.
Conclusions: The present findings suggest that RSV infection increases the number of DCs and the cysLT concentrations in lung tissues of asthma patients, both of which could result in enhanced allergic airway inflammation.

抄録全体を表示

Background: CC chemokines have been shown to play an important role in inducing selective recruitment of inflammatory cells into local allergic inflammatory sites. CC chemokines are also known as histamine releasing factors. We previously showed that histamine enhances transcription of CC chemokines from nasal mucosa which leads to further induction of histamine release. This cyclic cascade may cause prolonged allergic inflammation. The aim of this study is to clarify the relationship between histamine and CC chemokine production by using human nasal epithelial cells (HNECs) and to examine the potential of H1 receptor (H1R) antagonists in new therapeutic approaches for the treatment of nasal allergy.
Methods: HNECs were isolated from the nasal turbinates of patients diagnosed with nasal allergy. HNEC monolayers were cultured for 48 hours with or without histamine (10^-3 to 10^-5mol/L). Furthermore, an H1R antagonist, either carebastine or olopatadine, was added to the supernatant (10^-3 to 10^-7mol/L) 30 minutes before incubation with histamine. The expression of Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) in the culture media were measured by ELISA.
Results: The release of RANTES and MCP-1 was significantly upregulated by histamine compared with the control group. Both carebastine and olopatadine inhibited the release of CC chemokine production to the control level in both groups.
Conclusions: This study suggests that the interaction between histamine and CC chemokines may prolong allergic inflammation in human nasal mucosa. We also demonstrate the potential use of H1R antagonists in new therapeutic approaches to the treatment of nasal allergy through inhibiting this histamine-CC chemokine interaction.

抄録全体を表示

The Impact of the Chuetsu Earthquake on Asthma Control

抄録全体を表示