Kinya Nagata

Saitama Cancer Center, Saitama, Saitama, Japan

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Publications (65)291.87 Total impact

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    ABSTRACT: Eosinophils appear to be key cells in the pathogenesis of conjunctival inflammation in atopic keratoconjunctivitis (AKC). Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) mediates prostaglandin D2 (PGD2)-dependent migration of eosinophils. However, it is unclear whether CRTH2/PGD2-dependent eosinophil migration is upregulated in allergic diseases. To compare the chemotactic responses of peripheral blood eosinophils to prostaglandin D2 in patients with severe AKC and healthy individuals. We used an enzyme immunoassay system to measure PGD2 levels in tears and blood samples from healthy individuals and patients with AKC. CRTH2 expression on peripheral blood eosinophils was determined using reverse-transcriptase polymerase chain reaction (RT-PCR), flow cytometry, and an oligonucleotide array system. Chemotaxis experiments were performed using a modified Boyden chamber technique and an optical assay system. The PGD2 concentrations were higher in tears from patients with severe AKC compared with healthy individuals. RT-PCR (severe and mild cases), flow cytometry (mild cases), and GeneChip analyses revealed a significantly higher expression of CRTH2 on peripheral blood eosinophils in patients with AKC than in healthy individuals. PGD2 and its stable metabolite 13,14-dihydro-15-keto-PGD2, a CRTH2 agonist, induced chemotaxis of eosinophils from patients with AKC; chemotaxis was significantly enhanced in eosinophils from patients with severe AKC compared with those from healthy individuals. CRTH2 is more abundantly expressed on eosinophils from patients with AKC and promoted PGD2-dependent migration to a greater extent than in healthy individuals.
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 08/2013; 111(2):126-131.e4. · 3.45 Impact Factor
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    ABSTRACT: Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD(2) and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2(-/-)) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2(-/-) mice, blunting CLP-induced lethality in CRTH2(-/-) mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH2(-/-) mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2(-/-) mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis.
    The Journal of Immunology 04/2012; 188(11):5655-64. · 5.52 Impact Factor
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    ABSTRACT: Prostaglandin D2 (PGD2) exerts its effects through two distinct receptors: the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the D prostanoid (DP) receptor. Our previous study demonstrated that CRTH2 mediates contact hypersensitivity (CHS) in mice. However, the function of DP receptor remains to be fully established. In this study, we examine the pathophysiological roles of PGD2 using DP-deficient (DP(-/-)) and CRTH2/DP-deficient (CRTH2(-/-)/DP(-/-)) mice to elucidate receptor-mediated PGD2 action in CHS. We observed profound exacerbation of CHS in DP(-/-) mice. CRTH2(-/-)/DP(-/-) mice showed similar exacerbation, but to a lesser extent. These symptoms were accompanied by increased production of interferon-γ and IL-17. The increase in IL-17 producing γδ T cells was marked and presumably contributed to the enhanced CHS. DP deficiency promoted the in vivo migration of dendritic cells to regional lymph nodes. A DP agonist added to DCs in vitro was able to inhibit production of IL-12 and IL-1β. Interestingly, production of IL-10 in dendritic cells was elevated via the DP pathway, but it was lowered by the CRTH2 pathway. Collectively, PGD2 signals through CRTH2 to mediate CHS inflammation, and conversely, DP signals to exert inhibitory effects on CHS. Thus, we report opposing functions for PGD2 that depend on receptor usage in allergic reactions.
    American Journal Of Pathology 07/2011; 179(1):302-14. · 4.52 Impact Factor
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    ABSTRACT: Granulysin (GNLY) is a novel cytolytic protein lytic against a variety of tumor cells and microbes. The role of GNLY during pregnancy has not been extensively explored. The aim of this study is to examine GNLY expression and distribution in the first trimester pregnancy peripheral blood (PB) and decidua, the ability of decidual and PB natural killer (NK) cells to secrete GNLY spontaneously, and the role of antigen-presenting cells (APC) in the regulation of GNLY expression in decidual NK cells. GNLY expression was analyzed using cell permeabilization method, flow cytometry, and immunohistochemistry. GNLY secretion by purified NK cells was detected by ELISA method. GNLY is abundantly expressed at the maternal-fetal interface in the first trimester pregnancy. Decidual T lymphocytes express significantly higher levels of GNLY (58%) then PB T lymphocytes (11%). Over 85% of decidual CD56(+) cells express GNLY and when cultured spontaneously release high quantities of GNLY. Decidual APC participate in the control of GNLY expression in CD56(+) cells. Abundant expression of GNLY in the decidual immunocompetent cells and the capacity of decidual CD56(+) cells to spontaneously secrete high quantities of GNLY point to important protective and immunomodulatory role that this molecule could play at the maternal-fetal interface.
    American Journal Of Reproductive Immunology 05/2011; 66(5):363-72. · 3.32 Impact Factor
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    ABSTRACT: In patients with refractory infections, reliable markers that monitor the severity and healing process are needed. The expression level of toll-like receptor 2 (TLR2) on monocytes is such candidate. In the conventional assay system, the whole IgG (wIgG) form of anti-TLR2 mAb has been used with control IgG, which blocks nonantigen-specific bindings. However, the competitive reactions against Fcγ receptors (FcγRs) between labeled anti-TLR2 mAbs and control IgG should be considered. Our goal was to precisely quantify TLR2 expression level on monocytes by flow cytometry (FCM). In this study, we prepared anti-TLR2 mAbs, D45 (IgG2a), and D29 (IgG1), as well as their fragment antigen-binding [F(ab')(2) ] fragments to avoid nonantigen-specific binding to FcγRs. And then, we determined TLR2 expression levels on monocytes by using these mAbs/fragments and our calibration system using recombinant TLR2 beads. The binding of PE-labeled D45 wIgG to monocytes was completely blocked with unlabeled D45 wIgG, but not with unlabeled D45 F(ab')(2) fragment. Although the nonantigen-specific binding of D29 wIgG to nonstimulated monocytes was negligible, it was enhanced in interleukin-10-stimulated monocytes. It proved difficult to completely block nonantigen-specific binding of D45 and D29 wIgGs by treatment with control IgG. It was demonstrated that the use of fluorescent-labeled antigen-binding region lacking the fragment crystallizable portion of anti-TLR2 mAb [such as the PE-labeled F(ab')(2) fragment] is indispensible for quantification of TLR2 levels on monocytes in flow cytometry. .
    Cytometry Part A 04/2011; 79(4):247-55. · 3.71 Impact Factor
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    ABSTRACT: The prostaglandin D(2) (PGD(2))/CRTH2 pathway is important for eosinophil trafficking in vitro; however, genetic deficiency of CRTH2 does not suppress in vivo eosinophilic airway inflammation in acute models of asthma, and the role of CRTH2 in the pathogenesis of asthma is still ambiguous. Therefore, in the present study we explored whether the PGD(2)/CRTH2 pathway could affect the phenotypes of chronic asthma. Either CRTH2-deficient (CRTH2-/-) or wild-type mice were sensitized and exposed to ovalbumin (OVA) for 3 days (acute model) or 6 weeks (chronic model). While the magnitude of the acute eosinophilic inflammation was equivalent between CRTH2-/- and wild-type mice, the number of inflammatory cells and eosinophils in bronchoalveolar lavage fluid after chronic OVA exposure was significantly reduced in CRTH2-/- mice (18.0 ± 2.6 × 10(4) cells and 2.0 ± 0.5 × 10(4) cells) compared to wild-type mice (27.9 ± 2.5 × 10(4) cells and 6.8 ± 1.1 × 10(4) cells, p < 0.001). On the contrary, no difference was observed between CRTH2-/- and wild-type mice in terms of airway hyperresponsiveness or remodeling (goblet cell hyperplasia) in the chronic model of asthma. In conclusion, CRTH2 that mediates PGD(2) activity is essential for sustained eosinophilic inflammation in the airways, and its antagonists could exert an anti-inflammatory effect in chronic asthma.
    International Archives of Allergy and Immunology 01/2011; 155 Suppl 1:6-11. · 2.25 Impact Factor
  • British Journal of Haematology 11/2009; 148(5):812-4. · 4.94 Impact Factor
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    ABSTRACT: Immunological responses in the host can result in different disease outcomes of Helicobacter pylori-induced gastritis. Prostaglandin E2 derived from cyclooxygenase (COX) and prostaglandin E synthase contribute to gastric protection. Recently, prostaglandin D2 was shown to be involved in host immunity by chemotactic activity through chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), but its role in H. pylori-induced gastritis has not been clarified. We determined the expression levels of mRNAs for haematopoietic PGD synthase (H-PGDS) and lipocalin-type PGDS (L-PGDS), MIP-1 alpha, IFN-gamma, IL-4, and CDX2 in H. pylori-induced gastritis mucosa by quantitative RT-PCR. We found that L-PGDS was constitutively expressed in the epithelium of the glandular base. L-PGDS, but not H-PGDS, was induced on fibroblasts close to infiltrating cells in the H. pylori-infected gastric mucosa. These fibroblasts co-expressed COX-2. The level of L-PGDS mRNA expression decreased as gastritis became more severe. In most of the H. pylori-infected gastric mucosa, CCR5(+) cells had more actively infiltrated than had CRTH2(+) cells. However, the expression level of IFN-gamma was lower in the mucosa of the CRTH2(+) cells-dominantly infiltrating group than that of the less CRTH2-infiltrating group. Exogenously added PGD2 decreased the H. pylori-induced expression of IFN-gamma in peripheral blood mononuclear cells in vitro. The data suggest that PGD2 derived from the gastric mucosa and fibroblasts plays protective roles against inflammatory changes in H. pylori-induced gastritis.
    The Journal of Pathology 08/2009; 219(4):417-26. · 7.59 Impact Factor
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    ABSTRACT: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns to initiate an innate immune response. We previously reported upregulation of TLR2 expression level on monocytes of stable angina pectoris patients with significant coronary artery disease (CAD) relative to control patients without significant CAD. In this study we aimed to determine whether high level of Toll-like receptor 2 (TLR2) is a risk factor for atherogenesis, independent of established risk factors including smoking, diabetes mellitus (DM), hypertension (HT), and hyperlipidemia (HL). TLR2 expression level on circulating monocyte surfaces was measured by using our developed flow cytometry assay. Patients were classified into two groups: "Arteriosclerotic disease" group (n=108) and "Control" group (n=70). Patients of the first group had arteriosclerotic disease such as CAD, aortic aneurysm, or peripheral arterial disease (PAD). The "Control" group was sex- and age-matched to the "Arteriosclerotic disease" group. TLR2 expression was significantly higher in the "Arteriosclerotic disease" group than in the "Control" group (p<0.001). Multivariate ordinal logistic regression analysis was performed; other known risk factors, which were represented to two nominal score points, 0 or 1, for patients with and without it, respectively, and TLR2 level, which was treated as a metric variable. DM (p=0.002), HT (p=0.001), HL (p<0.001), and TLR2 level (p<0.001) were identified as significant contributors for arteriosclerotic disease. High TLR2 expression level on monocytes may be an independent risk factor for atherogenesis.
    Atherosclerosis 08/2009; 209(1):248-54. · 3.71 Impact Factor
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    ABSTRACT: Many studies have suggested that inflammation may participate in the pathogenesis of non-valvular atrial fibrillation (AF). However, it has been unknown by exposure to what the inflammation is caused. Recently, we reported that Toll-like receptor 2 (TLR2) level on monocytes was significantly up-regulated in viral and bacterial infections, but not in non-infectious inflammatory states. Our purpose was to test the hypothesis that expression of TLR2 levels may be up-regulated in patients with non-valvular AF. A total of 48 consecutive patients with non-valvular AF who were hospitalized for catheter ablation were enrolled in this study. TLR2 levels were assayed by using flow-cytometric analysis and compared with volunteers in sinus rhythm (control group, n = 24). Additionally, C-reactive protein (CRP) and interleukin-6 (IL-6) levels were assayed, and the left atrial volume indexes (LAVI) in the non-valvular AF group were measured. The results demonstrated that TLR2 levels in the non-valvular AF group were significantly higher than in the control group (median, 4682 vs. 3866 sites/cell; P < 0.01). Moreover, non-valvular AF patients had significantly higher IL-6 levels than controls. However, there was no significant difference in CRP levels between the two groups. It was observed in 44 AF patients, in whom pulmonary vein isolation was confirmed to be successful, that the LAVI significantly diminished 1 month after ablation (median, 33.6 vs. 29.5 ml/m²; P < 0.001), but not the TLR2 and IL-6 levels. Our results implied that an infectious inflammation may participate in the pathogenesis of non-valvular AF.
    Journal of Cardiology 02/2009; 53(1):127-35. · 2.30 Impact Factor
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2009; 123(2).
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    ABSTRACT: Immune changes are known to occur in recurrent spontaneous abortion, but it is unclear whether either maternal natural killer (NK) cells or T cells attack fetus-derived trophoblasts. To clarify the immunological causes of spontaneous abortion, we examined the relationship between cytotoxic granule proteins in decidual lymphocytes, such as granulysin, granzyme B, and perforin, and the induction of apoptosis in extravillous trophoblasts (EVTs). The number of granulysin-positive CD56(bright) NK cells increased significantly in the decidua basalis during spontaneous abortion compared with normal pregnancy; however, granzyme B- and perforin-positive cells did not change. Interestingly, the expression of granulysin was also detected in the nuclei of EVTs in spontaneous abortion samples. When IL-2-stimulated CD56(bright) NK cells were cocultured with EVT cells (HTR-8/SV40neo), granulysin was found initially in the cytoplasm and then accumulated in the nuclei of the HTR-8/SV40neo cells. Furthermore, transfected cells expressing a GFP-granulysin fusion protein induced apoptosis in HTR-8/SV40neo cells independently of caspases. Our results suggest that granulysin-positive uterine NK cells attack EVTs; subsequently, the uNK-derived granulysin actively accumulates in the nuclei of EVTs, causing the death of EVTs due to apoptosis. These data support a new apoptosis pathway for trophoblasts via uNK-derived granulysin, suggesting that granulysin is involved in spontaneous abortion.
    American Journal Of Pathology 10/2008; 173(3):653-64. · 4.52 Impact Factor
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    ABSTRACT: For viral infectious diseases, reliable biomarkers capable of monitoring recovery and therapeutic effects and that simultaneously discriminate between viral and bacterial infection are necessary. In this study, by using flow-cytometric quantification system, Toll-like receptor 2 (TLR2) expression levels on monocytes of influenza patients (n=47) were compared with those of healthy volunteers (n=50). Subsequently, throughout their acute, convalescent and healed phases, TLR2, C-reactive protein (CRP), serum amyroid A (SAA), and neopterin levels were followed. Additionally, TLR2 levels in other viral infectious diseases were assayed. The results showed that TLR2 level in influenza patients was remarkably up-regulated in acute phase compared to healthy volunteers (p<0.001). Thereafter, TLR2 levels normalized in good accordance with their recovery processes. CRP and neopterin levels were relatively widely distributed from normal to abnormally high levels in acute phase in spite of similar disease severity among the patients. SAA levels did not necessarily reflect the patients' clinical course during their recovery. Clinical observations of other viral infections also indicated that TLR2 levels were compatible with infection severity. TLR2 expression level on monocytes might serve as a unique biomarker useful in viral infectious diseases.
    The Journal of infection 09/2008; 57(3):249-59. · 4.13 Impact Factor
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    ABSTRACT: PGD(2) is the major prostanoid produced during the acute phase of allergic reactions. Two PGD(2) 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 PGD(2)-CRTH2 interaction is elevated following sensitization and plays a proinflammatory role in the pathophysiology of allergic rhinitis, especially pollinosis in mice.
    The Journal of Immunology 05/2008; 180(8):5680-8. · 5.52 Impact Factor
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    ABSTRACT: Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness.
    The Journal of Immunology 02/2008; 180(1):541-9. · 5.52 Impact Factor
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2008; 121(2).
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    ABSTRACT: The clinical course of bacterial infectious diseases is often variable, especially in elderly patients. Thus, new biological markers have been sought to predict the disease outcome. Recent studies have revealed that Toll-like receptor (TLR) 2 and/or TLR4 on circulating monocytes are significantly up-regulated in bacterial infections. However, the lack of reliable quantification methods hampers extensive study on the modulation of these molecules in response to the patient's clinical condition. In this study, we developed a new quantitative flow cytometric analysis system for TLR2. We then carried out a longitudinal study on TLR2 expression levels on monocytes from patients suffering from bacterial infectious diseases during and after antibiotic treatment. The clinical outcome divided 37 patients into 'cure' (n = 24) and 'recurrence' (n = 13) groups. A significant difference between the two groups was recognized in the TLR2 levels just after antibiotic treatment (antibody-binding sites/cell, 4395 +/- 784 versus 5794 +/- 1484, P < 0.001). The risk of recurrence was associated significantly with TLR2 (P < 0.001), but not C-reactive protein (P = 0.351) levels assayed during the first remission. Furthermore, antibiotic effectiveness was associated inversely with TLR2 levels during antibiotic administration (P < 0.001). Taken together, TLR2 expression levels on monocytes provide critical information for planning treatment against bacterial infectious diseases.
    Clinical & Experimental Immunology 05/2007; 148(2):260-70. · 3.41 Impact Factor
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    ABSTRACT: Epidemiological, clinical and histological data suggest intriguing similarities between preeclampsia and graft-host-rejection. Granulysin, a novel biomarker of overall cellular immunity, is secreted by natural killer cells and cytotoxic T lymphocytes, which are associated with graft-host-rejection. Plasma granulysin was elevated in Japanese preeclamptic women. 50 preeclampsia cases and 50 normotensive controls (USA) were studied. Plasma granulysin at delivery was determined using enzyme immunoassay. Logistic regression procedures were used to estimate odds ratios (OR) and 95% confidence intervals (CI). Granulysin were elevated in preeclampsia cases compared with controls (3.01+/-0.18 vs. 2.22+/-0.14 ng/mL, p<0.01). After adjusting for age, body-mass-index and race, women with higher granulysin concentrations (> or =1.89 ng/mL) experienced a 2.9-fold (95%CI 1.1-7.8) increased preeclampsia risk compared with women with lower granulysin (<1.89 ng/mL). These data offer further evidence of a predominant Th1 immune status associated with preeclampsia. Prospective studies are needed to determine whether granulysin is elevated early in pregnancy.
    Clinical Biochemistry 11/2006; 39(10):1016-21. · 2.45 Impact Factor
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    ABSTRACT: The circulating number of natural killer (NK) cells largely changes after an acute bout of physical exercise. Granulysin is a cytolytic granule protein with a broad range of antimicrobial and tumoricidal activities produced and released by human NK cells and cytolytic T lymphocytes. Since NK cells constitutively produce granulysin, most serum granulysin in healthy humans is derived from NK cells. Serum graulysin levels in the healthy humans may therefore reflect the size of whole-body NK cell population in the body. The aim of this study was to determine the effect of an acute bout of exhaustive exercise on serum granulysin in comparison with the circulating number of NK cells. Six healthy, young male volunteers participated in the study. Each subject underwent both exhaustive exercise and resting sessions in a random order with at least a seven-day interval. Subjects were asked to run to exhaustion on a treadmill with an incremental graded protocol. Blood samples were collected before, immediately after, and 1 hr, 3 hr, 6 hr, 12 hr and 24 hr after exercise. Serum granulysin levels were measured by enzyme-linked immunosorbent assay (ELISA). NK cells were determined by flow cytometry. Exhaustive exercise induced a 4.8-fold increase in peripheral blood NK cells, but no significant change in serum granulysin. Our results support the hypothesis that exhaustive exercise-induced changes in the circulating number of NK cells represent a redistribution of lymphocytes, rather than the change in the size of whole-body NK cell population.
    The Tohoku Journal of Experimental Medicine 11/2006; 210(2):117-24. · 1.37 Impact Factor
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    ABSTRACT: PGD(2) plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35-55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD(2)-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.
    The Journal of Immunology 09/2006; 177(4):2621-9. · 5.52 Impact Factor

Publication Stats

2k Citations
129 Downloads
291.87 Total Impact Points

Institutions

  • 2011
    • Saitama Cancer Center
      Saitama, Saitama, Japan
  • 2008–2009
    • Kagoshima University
      Kagosima, Kagoshima, Japan
  • 2006
    • Tokyo Medical and Dental University
      • Department of Dermatology
      Edo, Tōkyō, Japan
  • 2001–2004
    • Toyama Medical and Pharmaceutical University
      Тояма, Toyama, Japan
  • 1989–1992
    • Tohoku University
      • Department of Microbiology and Immunology
      Sendai, Kagoshima, Japan