Yuji Sugata

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.

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.

Role of prostaglandin D2 and E2 terminal synthases in chronic rhinosinusitis

Background Prostaglandin (PG)D2 and E2, two major cyclooxygenase (COX) products, are generated by PGD2 synthase (PGDS) and PGE2 synthase (PGES), respectively, and appear to mediate airway inflammation.

Nasal exposure to Staphylococcal enterotoxin enhances the development of allergic rhinitis in mice

Background Staphylococcal enterotoxins (SEs) appear to play a role in the pathogenesis of allergic disease. However, little is known whether the nasal exposure to SE affects the development of allergic rhinitis (AR).

Histamine H4 receptor agonists have more activities than H4 agonism in antigen‐specific human T‐cell responses

Histamine not only mediates immediate allergic reactions, it also regulates cellular immune responses. H4R is the most recently identified histamine receptor (HR). In the present study, we examined the in vitro effect of histamine and H4R agonists on the responses of human T cells to purified protein derivative from Mycobacterium tuberculosis (PPD) and to Cry j1, the major allergen of Cryptomeria japonica pollen. Dimaprit, clobenpropit and clozapine, which are H4R agonists, dose‐dependently blocked both PPD‐induced interferon‐γ and Cry j1‐induced interleukin‐5 production by both peripheral blood mononuclear cells (PBMCs) and antigen‐specific T‐cell lines. However, the addition of thioperamide, an H3R/H4R antagonist, as well as a mixture of d‐chlropheniramine, famotidine and thioperamide, did not reverse the inhibition. Pretreatment of PBMCs with SQ22536 and 8‐bromoadenosine‐3′,5′‐cyclic monophosphorothioate, Rp‐isomer, had varying abilities to reverse the inhibitory effects of H4R agonists, except for clobenpropit. Moreover, the addition of H4R agonists induced annexin‐V expression on PBMCs, especially in CD19+ and CD4+ cells. cDNA microarray analysis revealed that, among 16 600 genes tested, increased expression following treatment with clozapine was seen in 0·8% of the genes, whereas decreased expression was seen in 3·0% of the genes. These results suggest that H4R agonists inhibit antigen‐specific human T‐cell responses, although H4R does not appear to be important for this effect. In addition, the present study indicated that there may be orphan receptors or HR subtypes which can bind dimaprit, clobenpropit and clozapine, and that can exert an inhibitory effect on antigen‐specific cellular responses via a cAMP/cAMP‐dependent protein kinase‐dependent, apoptotic pathway.

TH1/TH2 and regulatory cytokines in adults with otitis media with effusion.

Objective: Otitis media with effusion is one of the most common and intractable ear diseases. However, the role of Th1, Th2, and immunoregulatory cytokines on the pathogenesis of the disease in adult patients remains to be determined. The aim of this study is to disclose the cytokine expression in middle ear effusions (MEEs) in adults and to compare the profile on the basis of the presence of allergic rhinitis and the type of effusions. Study Design: A prospective controlled clinical study. Patients: MEEs were collected from 80 adult subjects. The concentration of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, and interferon (IFN)-&ggr; in MEEs were determined by using enzyme-linked immunosorbent assay. Results: IL-2, IL-4, IL-5, IL-10, IL-12, and IFN-&ggr; in MEEs were detected in 60 (75.0%), 33 (41.3%), 42 (52.5%), 14 (17.5%), 80 (100%), and 66 (82.5%) samples, respectively. Among these cytokines, only the concentration of IL-4 in the allergic rhinitis-positive group was significantly higher than that in the allergic rhinitis-negative group. On the other hand, IL-2, IL-12, and IFN-&ggr; were detected, regardless of the presence of allergic rhinitis, and the concentration of these cytokines correlated with each other. The correlation between the concentration of IL-4 and IL-5 was also detected. In addition, both the incidence rate and the concentration of IL-10 in MEEs were significantly higher in the mucoid type compared with those in the serous type effusions. Conclusion: Regardless of allergic status, IL-12 may play a critical role in the pathogenesis of otitis media with effusion by affecting the production of IL-2 and IFN-&ggr;. In addition, IL-4 may have some impact on the immunologic condition in adults with allergic rhinitis. IL-10 potentially affects the viscosity of MEEs.

The engraftment of transplanted bone marrow-derived cells into the olfactory epithelium

To investigate whether bone marrow cells migrate and are engrafted into the olfactory epithelium and differentiate into olfactory neurons, bone marrow cells of green fluorescence protein (GFP) mice were transplanted into lethally irradiated recipient mice. Immunohistochemical staining was performed to evaluate the engraftment of donor bone marrow cells into the olfactory epithelium. Immunostaining for GFP was found initially in the olfactory epithelium 2 weeks after bone marrow reconstruction. The percentage of GFP positive cells increased up to 12 months after bone marrow reconstruction. Double staining for GFP and olfactory marker protein showed that a population of the GFP-positive cells had characteristics of olfactory neurons. These results demonstrate that bone marrow cells can be engrafted in the olfactory epithelium and then differentiate into olfactory neuron cells.

Roles of major oligosaccharides on Cry j 1 in human immunoglobulin E and T cell responses

Background We have demonstrated that carbohydrates in Cry j 1, the major allergen of Cryptomeria japonica pollen, play a major role in promoting Cry j 1‐specific Th2 response. However, little is known as to whether the carbohydrates directly participate in allergic responses.

Allergen‐specific immunotherapy alters the expression of B and T lymphocyte attenuator, a co‐inhibitory molecule, in allergic rhinitis

Background B7/CD28 family co‐signalling molecules play a key role in regulating T cell activation and tolerance. Allergen‐specific immunotherapy (SIT) alters allergen‐specific T cell responses. However, the effect of SIT on the expression of various co‐signalling molecules has not been clarified.

Characterization of allergen-specific monocyte-derived dendritic cells generated from monocytes by a single-step procedure: effect on naïve and memory T cells

Background:  Dendritic cells are one of the most potent antigen‐presenting cells and when pulsed with allergen can modulate allergen‐specific T‐cell responses. We sought to establish a single‐step method by which to generate allergen‐specific monocyte‐derived dendritic cells (MoDCs).