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Journal of Investigative Dermatology 03/2012; 132(7):1925-7. · 6.31 Impact Factor
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ABSTRACT: Japanese cedar (Cryptomeria japonica; CJ) pollinosis is a typical type I allergy induced by CJ pollen and one of the most common allergic diseases in Japan. New immunotherapies have been developed for treatment of CJ pollinosis. We focus here on new immunotherapies for CJ pollinosis including sublingual immunotherapy with crude extract of CJ antigen, oral immunotherapy with transgenic rice expressing CJ allergens, a peptide vaccine using T cell epitopes of CJ allergens, DNA vaccines encoding either the CJ allergen gene or T cell epitope gene, and adjuvant-conjugated vaccines using CJ allergen conjugated with adjuvants such as CpG oligodeoxynucleotide or pullulan.
Auris, nasus, larynx 01/2011; 38(4):431-8. · 0.58 Impact Factor
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ABSTRACT: Formyl peptide receptor 1 (FPR1) and FPR2/ALX are known to control neutrophil chemotaxis in response to various ligands. In this study, we investigated the inhibitory mechanism of compound 43 (Cpd43), an FPR1 and FPR2/ALX dual agonist, on human neutrophil chemotaxis. Precedent stimulation of human peripheral blood neutrophils with Cpd43 rendered the cells unresponsive in calcium mobilization induced by interleukin-8, C5a, or leukotriene B₄. In addition, neutrophils pretreated with Cpd43 lost their chemotactic responses against these chemoattractants, wherein the expressions of chemoattractant receptors CXCR1, CXCR2, C5a receptor, and leukotriene B₄ receptor 1 on the surface of neutrophils were all diminished significantly by treatment with Cpd43. By evaluating its pharmacological effect on 341 molecules, including receptors and enzymes, we also confirmed that Cpd43 has a highly specific affinity to FPR1 and FPR2/ALX and does not show binding affinity to the other chemoattractant receptors. These results indicate a previously unrecognized inhibitory mechanism of Cpd43 on neutrophil chemotaxis: the induction of cross-desensitization of multiple chemoattractant receptors in human neutrophils through its FPR1 and FPR2/ALX dual agonism.
Journal of Pharmacological Sciences 01/2011; 115(1):63-8. · 2.08 Impact Factor
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ABSTRACT: It has been reported that the stimulation of neutrophils with N-formyl-Met-Leu-Phe (fMLF), an agonist for formyl peptide receptor (Fpr) 1, renders cells unresponsive to other chemoattractants in vitro. This is known as cross-desensitization, but its functional relevance in neutrophil migration in vivo has not been investigated. Here, we show that precedent stimulation of mouse neutrophils with compound 43, a non-peptidyl agonist for mouse Fpr1 and Fpr2, rendered the cells unresponsive to a second stimulation with C5a, leukotriene B₄, or keratinocyte-derived cytokine (KC) in calcium mobilization and chemotaxis assays in vitro. The expression of chemokine (C-X-C motif) receptor 2 (CXCR2) on the surface of neutrophils was concomitantly diminished by stimulating the cells with the compound. Moreover, oral administration of the compound to mice before they were exposed to lipopolysaccharide (LPS) aerosol resulted in a dose-dependent reduction in the neutrophil count in bronchoalveolar lavage fluid. The expression of CXCR2 on blood neutrophils was also reduced in the compound-administered mice. The recipient mice that underwent adoptive transfer of fluorescence-labelled neutrophils that had been incubated with the compound showed a substantial decrease in neutrophil counts in bronchoalveolar lavage fluid after they were exposed to LPS, when compared with the control mice to which vehicle-treated neutrophils had been transferred. These results are consistent with the idea that the agonist for Fpr1 and Fpr2 induced cross-desensitization in neutrophils and attenuated neutrophil migration into the airways. Our results also revealed the unpredicted effect of an Fpr1 and Fpr2 dual agonist, which may act as a functional antagonist for multiple chemoattractant receptors in vivo.
Immunology 10/2010; 132(3):441-50. · 3.32 Impact Factor
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ABSTRACT: CC chemokine ligand 17 (CCL17/thymus and activation-regulated chemokine: TARC) and CCL22 (macrophage-derived chemokine: MDC) selectively bind to CC chemokine receptor 4 (CCR4). The CCR4 system is considered to be responsible for the pathology of allergic diseases such as atopic dermatitis. To find and develop potential medicines against allergic diseases, we screened an in-house library to search for compounds having a profile as a CCR4 antagonist. From among the screening hits, we focused on 3-{2-[(2R)-2-phenyl-4-(4-pyridin-4-ylbenzyl)morpholin-2-yl]ethyl}quinazoline-2,4(1H,3H)-dione (named RS-1154), which had been newly synthesized in our laboratory. This compound inhibited the binding of [(125)I]CCL17 to human CCR4-expressing CHO cells with an IC(50) value of 27.7 nM and moreover inhibited CCL17-induced migration of DO11.10 mice-derived T helper 2 cells with an IC(50) value of 1.5 nM in vitro. We then examined the effect of RS-1154 in an ovalbumin-induced ear swelling assay. The ear thickness was decreased by intravenous administration of anti-CCL17 or anti-CCL22 antibodies, suggesting that the CCR4 system is involved in the ear swelling. Though partially, the oral administration of RS-1154 also significantly ameliorated the ear swelling at the doses of 30 and 100 mg/kg. Furthermore, the serum level of interleukin-4 decreased after the administration of RS-1154. In this study, we succeeded in obtaining a newly-synthesized compound, RS-1154, which has a potential to inhibit the chemotaxis of T helper 2 cells in vitro and to ameliorate ovalbumin-induced ear swelling in vivo. These results raise the possibility that RS-1154 or one of derivatives might become a therapeutic agent for atopic dermatitis patients.
European journal of pharmacology 10/2009; 624(1-3):38-44. · 2.59 Impact Factor
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ABSTRACT: A pyrazolone compound acting as a formyl peptide receptor (FPR) 2/ALX-selective agonist has been reported, but its pharmacological activities on human FPRs (hFPRs) and mouse FPRs (mFprs) have not been well demonstrated. In this study, we found that this compound, designated as compound A, induced concentration-dependent calcium flux not only in Chinese hamster ovary (CHO) cells expressing hFPR2/ALX but also in cells expressing hFPR1, mFpr1, or mFpr2. It also induced the receptor internalization of hFPR1 and hFPR2/ALX and, accordingly, induced calcium influx and chemotactic responses in both human and mouse neutrophils. Our study revealed that compound A is in fact an FPR1 and FPR2/ALX dual agonist.
Journal of Pharmacological Sciences 01/2009; 111(3):317-21. · 2.08 Impact Factor
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ABSTRACT: Sublingual immunotherapy using allergen-derived peptides is feasible as a novel specific immunotherapy, but its efficacy has not yet been demonstrated in either humans or animals. In addition, it remains obscure whether the oral immune system is involved in the mechanism of sublingual immunotherapy. Here, we show that the intraoral administration of the T-cell epitope peptide P2-246-259 derived from Cry j 2, a major Japanese cedar (Cryptomeria japonica) pollen allergen, to Cry j 2-sensitized mice induces immunological tolerance, and that ex vivo lymph node cell proliferation to P2-246-259 and Cry j 2 was inhibited. In addition, intraoral administration was shown to be superior to intragastric administration in terms of tolerance induction, suggesting that the oral immune system contributes to the induction of immunological tolerance. Therefore, the significant efficacy of sublingual immunotherapy using a peptide on allergen-specific T-cells was demonstrated in animals, and this may be potentiated by the oral mucosal immune system.
Journal of Peptide Science 09/2007; 13(8):499-503. · 1.80 Impact Factor
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ABSTRACT: Although the concept of a T cell epitope in specific immunoprophylaxis was proposed more than a decade ago, it had not been well demonstrated since then that a T cell epitope inhibits symptoms and reactions of allergic disease in animal models. In this study, we have established a system to evaluate symptoms and reactions of allergic rhinitis in mice, and investigated whether oral administration of a T cell epitope relieves sensitized mice of allergic rhinitis. P2-246-259 (RAEVSYVHVNGAKF) is a BALB/c mouse T-cell epitope of Cry j 2, which is a major Japanese cedar (Cryptomeria japonica) pollen allergen. Mice were administered orally with 200 microg/animal of P2-246-259 four times within 2 weeks before sensitization, and sensitized intranasally with Cry j 2 twice. Of the cardinal symptoms of allergic rhinitis, we assessed sneezing and airway obstruction, but could not estimate rhinorrhea or pruritus. Sneezing frequency was significantly increased by challenge with Cry j 2. Concerning allergic reactions, vascular permeability of the nasal mucosa in the early phase and hyperreactivity to histamine in the late phase were also exacerbated by the challenge. These symptoms and reactions of allergic rhinitis were significantly inhibited by oral administration of P2-246-259. These results indicate utility of mice as models for allergic rhinitis; furthermore, the effects of P2-246-259 on allergic rhinitis imply that oral administration of a T cell epitope is a promising approach for specific immunoprophylaxis.
European Journal of Pharmacology 04/2005; 510(1-2):143-8. · 2.52 Impact Factor
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Eiichiro Sato, Kazuki Hirahara,
Yoshihiro Wada,
Tomomi Yoshitomi,
Takachika Azuma,
Kunie Matsuoka,
Shuichi Kubo,
Choji Taya,
Hiromichi Yonekawa,
Hajime Karasuyama,
Akio Shiraishi
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ABSTRACT: It is now widely accepted that IgE mediates immediate-type allergic response. However, the pathologic role of IgE is controversial in the chronic allergic inflammation observed in atopic diseases, such as asthma and atopic dermatitis.
We investigated the role of IgE in cutaneous allergic reactions by using 2 newly developed lines of antigen-specific IgE transgenic mice.
IgE transgenic mice were administered subcutaneously with corresponding antigens, and the subsequent ear swelling was measured.
A single subcutaneous administration of TNP-conjugated ovalbumin (OVA) into the ears of nonimmunized mice carrying the TNP-specific IgE transgene elicited immediate-phase and late-phase ear swelling as expected, which peaked at 20 minutes and 8 hours later, respectively. Interestingly, however, 2 to 3 days after the antigen challenge, more intense ear swelling appeared. Its magnitude and duration were dependent on the valency of TNP in OVA, as well as the dose of TNP-OVA, and it lasted over 1 month when 100 microg of OVA conjugated with 11 molecules of TNP was given. Interestingly, administration of OVA to OVA-specific IgE transgenic mice elicited immediate-phase and late-phase ear swelling but not third-phase ear swelling. Massive infiltration of inflammatory cells was observed in the third-phase ear swelling of TNP-specific IgE transgenic mice. Cyclosporine A almost completely inhibited the third-phase ear swelling and cellular infiltration, whereas an antihistamine, cyproheptadine, did not show any significant effect on the third-phase reaction.
These results indicate that IgE can trigger not only immediate-type hypersensitivity but also chronic allergic inflammation. Our findings highlight a novel immunopathologic role of IgE in chronic atopic disorders.
Journal of Allergy and Clinical Immunology 02/2003; 111(1):143-8. · 11.00 Impact Factor
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ABSTRACT: It has been demonstrated in detail that administration of a dominant T-cell determinant to animals induces activation or immunological tolerance of T cells. However, it has not been determined whether multiple T-cell determinants, when integrated into a single peptide, retain their potential to induce T-cell activation and tolerance. We prepared a synthetic peptide comprising three T-cell determinants of Cry j 1 and Cry j 2, the major Japanese cedar pollen antigens, and investigated the immunogenicity and tolerogenicity of each T-cell determinant in the linked peptide by means of lymph node cell proliferation assays using mice. Lymph node cells from mice immunized with each of the three T-cell determinants proliferated against the linked peptide in a dose-dependent manner, similar to that of the immunized peptide. Lymph node cells from mice immunized with the linked peptide proliferated against all of the three T-cell determinants. In addition, the degree of proliferation against the three T-cell determinants occurred according to their original immunogenicity, as observed in the native protein antigens. Oral administration of the linked peptide to mice before they were immunized with Cry j 1 and Cry j 2 inhibited lymph node cell proliferation against the three T-cell determinants, depending on the dose of the linked peptide administered. In conclusion, it was demonstrated that three T-cell determinants retain their original immunogenicity and tolerogenicity in a linked peptide comprising them.
Immunology 01/2003; 107(4):517-22. · 3.32 Impact Factor
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ABSTRACT: The natural occurrence of Japanese cedar [Cryptomeria japonica (CJ)] pollinosis has been reported in Japanese monkeys (Macaca fuscata). The present study was designed to investigate seasonal changes in immunological reactions to CJ pollen allergens in monkeys with CJ pollinosis. Blood samples were collected from six monkeys with CJ pollinosis before and after CJ pollen season. Seasonal changes in specific IgE and IgG to major allergens (Cry j 1 and Cry j 2) were observed before and after CJ pollen season. The humoral responses decreased significantly before CJ pollen and increased after CJ pollen season. Similar seasonal changes in peripheral blood mononuclear cells proliferative responses to CJ allergens were observed before and after CJ pollen season. These humoral and cellular immune responses might serve as a biomarker for assessing new immunotherapies for monkeys with pollinosis.
Journal of Medical Primatology 03/2001; 30(2):112 - 120. · 1.30 Impact Factor
