Mitsuhiro Okano

Lacto-N-fucopentaose III found on Schistosoma mansoni egg antigens functions as adjuvant for proteins by inducing Th2-type response.

We have recently demonstrated that induction of Th2 responses by Schistosoma mansoni egg Ag is largely due to carbohydrates on the Ag functioning as adjuvants. Lacto-N-fucopentaose III (LNFPIII), a polylactosamine sugar, is the predominant carbohydrate found in S. mansoni egg Ag. Therefore, using neoglycoprotein, we investigated whether LNFPIII induces in vivo Th2 response and functions as an adjuvant. Following intranasal immunization with LNFPIII linked to human serum albumin (HSA) (HSA-LNFPIII), BALB/c mice mounted a strong Th2 response and produced significantly higher levels of total IgE as well as HSA-specific IgG, IgG1, and IgE. HSA-LNFPIII was over 1000-fold more potent in inducing Ab production as compared with HSA alone. Although LNFPIII itself did not function as an epitope for either IgG or IgE, its conjugation with protein was essential for the adjuvant activity. Moreover, fucose residue on LNFPIII was crucial for induction of Ab production. Nasal lymphocytes from mice immunized with HSA-LNFPIII produced IL-4, IL-5, and IL-10, but not IFN-γ following in vitro stimulation with HSA or HSA-LNFPIII. In addition, these activated nasal lymphocytes also showed a significant increase of B7-2 expression on B220-positive cells. Furthermore, not only intranasal but also both i.p. and s.c. immunization with HSA-LNFPIII induced significant production of HSA-specific Abs compared with the immunization with HSA alone, suggesting that the activity of LNFPIII was not restricted on particular route of immunization. These results demonstrate that Lewis type carbohydrate LNFPIII can function as an adjuvant by their ability to induce a Th2 response.

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.

ENHANCED TH2-LIKE RESPONSES IN IL-1 TYPE 1 RECEPTOR-DEFICIENT MICE

IL‐1 has a number of effects on T cell growth but a specific role for IL‐1 in T cell responses in vivo has not been elucidated. In this study the role of IL‐1 in Th1/Th2 responses was examined in mice deficient for the IL‐1 type 1 receptor (IL‐1RI −/−) during cutaneous Leishmania major infection or following immunization with keyhole limpet hemocyanin (KLH). After inoculation of L. major stationary phase promastigotes into the hind footpad, both IL‐1RI−/− and wild‐type (WT) mice developed small lesions which resolved spontaneously. Lymphnode cells from infected IL‐1RI−/− mice produced significantly more IL‐4 and IL‐10 than those from WT mice following antigenic stimulation in vitro. Splenocytes from IL‐1RI−/− and WT mice showed similar levels of antigen‐induced proliferation. In contrast, splenocyte cultures from the IL‐1RI−/− mice contained significantly more IL‐4 than those from WT mice. Similar results were also obtained after immunization with KLH. While lymph node cells from both IL‐1RI−/− and WT mice displayed similar levels of KLH‐specific proliferation, those from IL‐1RI −/− mice produced significantly more IL‐4 than those from WT mice. Conversely, antigen‐stimulated lymph node cells from WT mice secreted significantly greater amounts of IFN‐γ as compared with those from IL‐1RI −/− mice. These data indicate that while IL‐1 is not required for mounting an immune response or antigen‐dependent proliferation, it appears to be required for normal regulation of Th1/Th2 responses and may function to negatively regulate IL‐4 expression.

A Randomized Double-Blind Comparative Study of Sublingual Immunotherapy for 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.

Strain-dependent induction of allergic rhinitis without adjuvant in mice

Background: To date, no murine models have been reported to show the induction of both antigen‐specific IgE and nasal eosinophilia, two of the major hallmarks of allergic rhinitis, after local sensitization in the absence of adjuvants, a phenomenon which reflects natural exposure. In this report, we attempted to establish a murine model representing an initiation of allergic rhinitis.

CRTH2 plays an essential role in the pathophysiology of Cry j 1-induced pollinosis in mice

PGD2 is the major prostanoid produced during the acute phase of allergic reactions. Two PGD2 receptors have been isolated, DP and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), but whether they participate in the pathophysiology of allergic diseases remains unclear. We investigated the role of CRTH2 in the initiation of allergic rhinitis in mice. First, we developed a novel murine model of pollinosis, a type of seasonal allergic rhinitis. Additionally, pathophysiological differences in the pollinosis were compared between wild-type and CRTH2 gene-deficient mice. An effect of treatment with ramatroban, a CRTH2/T-prostanoid receptor dual antagonist, was also determined. Repeated intranasal sensitization with Cry j 1, the major allergen of Cryptomeria japonica pollen, in the absence of adjuvants significantly exacerbated nasal hyperresponsive symptoms, Cry j 1-specific IgE and IgG1 production, nasal eosinophilia, and Cry j 1-induced in vitro production of IL-4 and IL-5 by submandibular lymph node cells. Additionally, CRTH2 mRNA in nasal mucosa was significantly elevated in Cry j 1-sensitized mice. Following repeated intranasal sensitization with Cry j 1, CRTH2 gene-deficient mice had significantly weaker Cry j 1-specific IgE/IgG1 production, nasal eosinophilia, and IL-4 production by submandibular lymph node cells than did wild-type mice. Similar results were found in mice treated with ramatroban. These results suggest that the PGD2-CRTH2 interaction is elevated following sensitization and plays a proinflammatory role in the pathophysiology of allergic rhinitis, especially pollinosis in mice.

E prostanoid 2 (EP2)/EP4‐mediated suppression of antigen‐specific human T‐cell responses by prostaglandin E2

Prostaglandin E2 (PGE2) is a lipid mediator that displays important immunomodulatory properties, such as polarization of cytokine production by T cells. Recent investigations have revealed that the effect of PGE2 on cytokine production is greatly influenced by external stimuli; however, it is unclear whether PGE2 plays a significant role in major histocompatibility complex‐mediated antigen‐specific T‐cell responses via binding to one of four subtypes of E prostanoid (EP) receptor alone or in combination. In the present study, we sought to determine the effect of PGE2 on antigen‐specific CD4+ T‐cell responses in humans, especially in terms of receptor specificity. We used purified protein derivative (PPD) and Cry j 1 as T helper type 1 (Th1) and Th2‐inducing antigens, respectively. We generated several different Cry j 1‐ and PPD‐specific T‐cell lines (TCLs). PGE2 significantly and dose‐dependently inhibited the proliferation and subsequent production of interleukin‐4 by Cry j 1‐specific TCLs and of interferon‐γ by PPD‐specific TCLs upon antigen stimulation. Administration of EP2 receptor agonist and EP4 receptor agonist suppressed these responses in an adenylate cyclase‐dependent manner, while EP1 and EP3 receptor agonists did not. Messenger RNA for EP2, EP3 and EP4, but not EP1, receptors were detected in Cry j 1‐ and PPD‐specific TCLs, and no differences in EP receptor expression were observed between them. Furthermore, PGE2 and EP2 receptor agonist significantly inhibited interleukin‐5 and interferon‐γ production by peripheral blood mononuclear cells in response to Cry j 1 and PPD stimulation, respectively. These results suggest that PGE2 suppresses both Th1‐ and Th2‐polarized antigen‐specific human T‐cell responses via a cAMP‐dependent EP2/EP4‐mediated pathway.

Sex-related differences in the initiation of allergic rhinitis in mice.

Background: Several clinical and epidemiologic studies have investigated sex differences in the prevalence of allergic rhinitis. At present, however, no reports have demonstrated such differences in experimental models with local, but not parenteral, sensitization with antigens that may reflect natural exposure to allergens. We have recently developed murine models of allergic rhinitis after repeated intranasal sensitization with antigens in the absence of adjuvants. In this study, we investigated the role of sex in the initiation of the disease in vivo.

Mechanisms and clinical implications of glucocorticosteroids in the treatment of allergic rhinitis

Allergic rhinitis is a common airway disease characterized by hypersensitivity, exudation, hypersecretion, inflammatory cell infiltration and remodelling. Intranasal glucocorticosteroids are the most effective drugs for controlling the inflammation caused by allergic rhinitis. Glucocorticosteroids exert anti‐inflammatory effects through at least two pathways: the transactivation pathway and the transrepression pathway. Glucocorticosteroids also exert regulatory functions by inducing regulatory cytokines and forkhead box P3 (FoxP3+) regulatory T cells. Evidence suggests that intranasal glucocorticosteroids control not only nasal symptoms but also ocular symptoms. In contrast to sedating H1 receptor antagonists, intranasal glucocorticosteroids can improve impaired performance symptoms, such as daytime sleepiness, associated with allergic rhinitis. Recent studies suggest that intranasal glucocorticosteroids might also be useful for the prophylactic treatment of pollinosis; this possibility is supported by the molecular mechanism of the anti‐inflammatory action of glucocorticosteroids. These findings suggest that intranasal glucocorticosteroids might be positioned as first‐line drugs for the treatment of both perennial and seasonal allergic rhinitis.

Presence and characterization of prostaglandin D2-related molecules in nasal mucosa of patients with allergic rhinitis

Background Prostaglandin D2 (PGD2) is the major prostanoid produced in the acute phase of allergic reactions. However, its pathophysiological role in addition to the pathway of production in allergic rhinitis remains unclear. We sought to determine the expression of synthases and receptors for PGD2 in human nasal mucosa. These expressions were compared between allergic and nonallergic patients. Methods The expression and localization of hematopoietic-type (h)-PGD2 synthase (PGDS) and lipocalin-type (l)-PGDS were detected by immunohistochemistry. The expression of D prostanoid (DP) receptor and chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) was determined by quantitative real-time PCR. Results The h-PGDS but not l-PGDS was clearly expressed in nasal mucosa. The expression of h-PGDS in allergic patients was significantly higher than in control patients without mucosal hypertrophy. A variety of infiltrating cells including mast cells, eosinophils, macrophages, and lymphocytes as well as constitutive cells such as epithelial cells and fibroblasts expressed h-PGDS. The expression of both DP and CRTH2 was confirmed also. Although either the amount of DP or the amount of CRTH2 was not correlated with serum levels of IgE, the amount of CRTH2 but not DP was highly and significantly correlated with the number of eosinophils infiltrating into nasal musosa. Conclusion These results suggest that PGD2 is released via the action of h-PGDS from various cells, and the expression of h-PGDS may be associated with the hypertrophic inflammation in the nose. In addition, ligation of PGD2 to CRTH2 appears to be selectively involved in eosinophil recruitment into the nose regardless of atopic status.