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Keywords:

  • artificial plantation;
  • Cha o 1;
  • Cha o 2;
  • early interventional treatment;
  • histamine H1 receptor antagonist;
  • IL-31;
  • IL-5;
  • immunotherapy;
  • Japanese cedar pollinosis;
  • Japanese cypress pollinosis

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Characterization of Japanese cypress pollen
  5. Pathophysiology of Japanese cypress pollinosis
  6. Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis
  7. Conclusions
  8. Acknowledgments
  9. References

In Japan, pollen from Japanese cedar (Cryptomeria japonica) and Japanese cypress (Chamaecyparis obtusa), species that have been planted in approximately 4.5 and 2.6 million ha, respectively, is spread wide through aerial dispersion in spring. Consequently, Japanese cedar/cypress pollinosis (JCCP) is the major phenotype of allergic rhinitis (AR) in Japan, and significantly impairs the quality of life (QOL). Compared with Japanese cedar pollinosis, the pathogenesis and management of Japanese cypress pollinosis remain unclear. Cha o 1 and Cha o 2 are major allergens in Japanese cypress pollen, and have considerable homology with Cry j 1 and Cry j 2, respectively, in Japanese cedar pollen. Several other components were recently identified in Japanese cypress pollen, and may facilitate allergic inflammation via IgE-independent mechanisms. Allergen-specific CD4+Th2 cells producing interleukin (IL)-4, IL-5, IL-13 and IL-31 are believed to play central roles in the pathogenesis of AR. The major human T cell epitopes in Cha o 1 and Cha o 2 have been identified. Compared with those in Cry j 1 and Cry j 2, both common and unique T cell epitopes in the cypress allergens have been characterized. Peripheral blood mononuclear cells (PBMCs) produced these Th2-type cytokines in response to a crude extract of Japanese cypress pollen. Among these cytokines, induction of antigen-specific IL-5 and IL-31 production is closely associated with the onset and exacerbation of Japanese cypress pollinosis, respectively. Allergen-specific immunotherapy using a standardized extract of Japanese cedar pollen is effective in controlling both naso-ocular symptoms and QOL during the period of cedar pollen dispersion, although the significant efficacy tends to be reduced during the period of cypress pollen dispersion, especially when the pollen dispersion is high. IL-5 production by PBMCs in response to the crude extract of Japanese cypress pollen did not differ significantly between patients with and without the immunotherapy, suggesting that unique component(s) in Japanese cypress pollen can induce IL-5 production, which is not fully suppressed by immunotherapy with the standardized extract of cedar pollen. The Practical Guideline for Management of Allergic Rhinitis in Japan recommends that patients who experience severe symptoms of pollinosis every year should receive early interventional treatment. Although early interventional treatment with a histamine H1 receptor antagonist (H1RA) is effective for Japanese cedar pollinosis, especially at the beginning of the season, this treatment has limitations for Japanese cypress pollinosis when exposure to the pollen is high. Combined therapy with a leukotriene receptor antagonist and/or intranasal corticosteroids may be required to fully control the worsening of JCCP during the cypress pollen season.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Characterization of Japanese cypress pollen
  5. Pathophysiology of Japanese cypress pollinosis
  6. Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis
  7. Conclusions
  8. Acknowledgments
  9. References

Allergic rhinitis (AR) is a common manifestation of allergic diseases. It affects approximately 500 million people worldwide and substantially impairs the quality of life (QOL) [1]. Japanese cedar/cypress pollinosis (JCCP) is the major phenotype of AR in Japan and has a prevalence of 29.8% [2]. JCCP is mainly caused by exposure to Japanese cedar (Cryptomeria japonica) pollen and Japanese cypress (Chamaecyparis obtusa) pollen (Fig. 1) [3]. The cypress pollen disperses after the cedar pollen in spring [4]. As the cedar pollen and cypress pollen contain several cross-reactive components, pollinosis-related symptoms can last for as long as 4 months, from February to early May [4-6].

image

Figure 1. Japanese cedar pollen (a, b) and Japanese cypress pollen (c, d). The cedar pollen and cypress pollen can be distinguished by the presence or absence of a papilla (arrow).

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The Practical Guideline for Management of Allergic Rhinitis in Japan (PG-MARJ) recommends that patients who experience severe pollinosis symptoms every year should receive early interventional treatment (i.e. prophylactic or initial treatment [2]. Double-blinded placebo-controlled trials have demonstrated that early interventional treatment with a histamine H1 receptor antagonist (H1RA) or leukotriene receptor antagonist (LTRA) is effective in controlling naso-ocular symptoms and/or QOL during the season when Japanese cedar pollen is dispersed [7, 8]. However, little is known about whether the treatment is effective for the season of Japanese cypress pollinosis.

In this review, we first discuss the characterization and pathogenesis of Japanese cypress pollinosis. We then review the effects of early interventional treatment with an H1RA on controlling Japanese cypress pollinosis.

Characterization of Japanese cypress pollen

  1. Top of page
  2. Summary
  3. Introduction
  4. Characterization of Japanese cypress pollen
  5. Pathophysiology of Japanese cypress pollinosis
  6. Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis
  7. Conclusions
  8. Acknowledgments
  9. References

Antigenic components of Japanese cypress pollen

Several components of Japanese cypress pollen have been identified as allergens and/or antigens that can regulate the pathophysiology of pollinosis. Cha o 1 and Cha o 2 are the major allergens in Japanese cypress pollen [9, 10]. The amino acid sequence of Cha o 1 consists of 354 residues and shows 79–80% homology with that of the corresponding Japanese cedar pollen component, Cry j 1, which has pectate lyase activity [9]. The amino acid sequence of Cha o 2 consists of 464 residues and shows 74.3% homology with that of the corresponding Japanese cedar pollen component, Cry j 2, which has polygalacturonase activity [10]. In fact, the serum IgE titres specific for Japanese cedar pollen are highly correlated with those specific for Japanese cypress pollen (r = 0.860, P < 0.001 by Pearson's correlation coefficient test), although the titres for cypress pollen are significantly lower than those for cedar pollen (P < 0.001 by Student's paired t-test, n = 46; Fig. 2). Other components including eicosanoid-like substances and NAD(P)H oxidase were recently identified in Japanese cypress pollen, and may facilitate allergic inflammation via IgE-independent mechanisms [11, 12]. In fact, the amount of LTB4-like substance is higher in Japanese cypress pollen than in Japanese cedar pollen [11]. The major allergens are glycoproteins, and we have determined the chemical structures of the N-glycans [13, 14]. Cha o 1 contains the N-glycan structure of GlcNAc2Man3Xyl1-Fuc1GlcNAc2 (89%) and high-mannose type (Man9GlcNAc2 and Man7GlcNAc2), and the proportion of the former glycan in Cha o 1 is almost double that in Cry j 1 [14].

image

Figure 2. Serum IgE titres specific for Japanese cedar pollen and Japanese cypress pollen in Japanese cedar/cypress pollinosis (JCCP) patients. (a) The serum IgE titres specific for Japanese cedar pollen and Japanese cypress pollen in JCCP patients (n = 46) were compared. The bars indicate the means. The P values were determined using Student's paired t-test. (b) The correlations between the serum IgE titres specific for Japanese cedar pollen and Japanese cypress pollen were determined by Pearson's correlation coefficient test.

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Dispersion of Japanese cypress pollen

In Japan, Japanese cedar is artificially planted in approximately 4.5 million ha while Japanese cypress is planted in approximately 2.6 million ha (http://www.rinya.maff.go.jp/j/hozen/kafun/data.html). The areas of Japanese cypress plantation are small (<10,000 ha/prefecture) in Hokkaido, Hokuriku and Tohoku districts except for Fukushima prefecture. On the contrary, other prefectures except for Tokyo metropolitan, Chiba and Okinawa prefectures have substantial areas (>10,000 ha) of Japanese cypress plantation. In particular, the areas of Japanese cypress plantation are larger than those of Japanese cedar plantation in most of the prefectures in Setouchi district. For example, the areas of Japanese cypress plantation are 2.9 times larger than those of Japanese cedar plantation in Okayama prefecture (Fig. 3a).

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Figure 3. Dispersion of Japanese cedar pollen and cypress pollen in Japan. (a) Areas of artificial Japanese cedar and cypress plantation in Japan. (b) Annual amounts of Japanese cedar pollen and cypress pollen dispersion in Okayama from 1997 to 2010.

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The total amount of Japanese cypress pollen dispersion during spring varies every year, since the amount of pollen is strictly affected by the amount of precipitation during the rainy season in the previous year [15]. High precipitation during the rainy season (June to July) is associated with lower dispersion of Japanese cypress pollen in the following year [16]. When we compared the amounts of annual dispersion between Japanese cedar pollen and cypress pollen from 1997 to 2010 in Okayama, the annual dispersion of Japanese cedar pollen was higher, albeit without statistical significance, than that of Japanese cypress pollen (P = 0.089 by Student's paired t-test). On the contrary, the annual dispersion of Japanese cypress pollen was higher than that of Japanese cedar pollen in 2000, 2006 and 2010 (Fig. 3b). Taken together with the fact that a large number of Japanese cypress trees were planted in the 1970s (http://www.rinya.maff.go.jp/j/hozen/kafun/data.html), these findings suggest that Japanese cypress pollinosis may become more widespread according to the increase in the dispersion of Japanese cypress pollen in the near future.

Pathophysiology of Japanese cypress pollinosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Characterization of Japanese cypress pollen
  5. Pathophysiology of Japanese cypress pollinosis
  6. Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis
  7. Conclusions
  8. Acknowledgments
  9. References

Peripheral blood mononuclear cell responses to Japanese cypress pollen

Allergen-specific CD4+ Th2 cells producing interleukin (IL)-4, IL-5 and IL-13 are believed to play central roles in the pathogenesis of AR [17-20]. Following nasal exposure to inhalant allergens, allergen-specific Th2 cells are generated in patients with AR, whereas allergen-specific Tr1 cells are generated in healthy individuals [18, 19]. Using overlapping peptides, 10 and 11 major human T cell epitopes have been identified in Cha o 1 and Cha o 2, respectively [6, 21]. In comparison with the T cell epitopes in Cry j 1 and Cry j 2, as the major allergens in Japanese cedar pollen, both common and unique T cell epitopes in the cypress allergens have been characterized. For example, four T cell epitopes in Cha o 1 do not cross-react with the corresponding epitopes in Cry j 1 [6].

We focused on the cellular responses of peripheral blood mononuclear cells (PBMCs) to a crude antigen extract of Japanese cypress pollen [22]. PBMCs from healthy controls did not produce IL-5 in response to the cypress crude antigen extract. On the contrary, PBMCs from 88.5% of JCCP patients produced IL-5 in response to the antigen extract (P < 0.001, vs. healthy controls by Fisher's exact probability test). PBMCs from 73.1% of the JCCP patients produced IL-13 in response to the antigen extract, compared with PBMCs from 37.5% of the healthy controls (P = 0.080). PBMCs from 57.7% of the JCCP patients produced interferon (IFN)-γ in response to the antigen extract, compared with PBMCs from 37.5% of healthy controls (P = 0.276). These findings suggest that the induction of antigen-specific Th2 cytokine production, especially IL-5, is closely associated with the onset of Japanese cypress pollinosis.

The IL-31 is a newly discovered cytokine that belongs to the Th2 cytokine family [23]. IL-31 is mainly produced by CD4+ T cells, particularly Th2 cells and skin-homing CD45RO+ cutaneous lymphocyte-associated antigen-positive cells [24, 25]. Therefore, the roles of IL-31 in allergic diseases such as atopic dermatitis and bronchial asthma have been examined [23-25]. PBMCs from healthy controls did not produce IL-31 in response to the cypress crude antigen extract. However, the JCCP patients group included both positive and negative responders in terms of IL-31 production (Fig. 4a). The amount of the cypress crude antigen extract-induced IL-31 production was significantly and positively correlated with the production of IL-5 (ρ = 0.754, P < 0.001) and IL-13 (ρ = 0.799, P < 0.001) but not IFN-γ (ρ = 0.355, P = 0.275). IL-31-producing PBMCs produced significantly higher amounts of IL-5 (P < 0.001) and IL-13 (P < 0.001) but not IFN-γ (P = 0.110), compared with IL-31-negative PBMCs. The QOL during cypress pollen dispersion was significantly impaired in patients who produced IL-31 in response to the cypress crude antigen extract, compared with patients who did not produce IL-31 (P = 0.007; Fig. 4b). In addition, the amount of IL-31 production in response to the cypress crude antigen extract was significantly and positively correlated with the QOL scores during the dispersion (ρ = 0.355, = 0.002). These findings suggest that, although cypress pollen antigen-induced IL-31 production is not essential for the onset of Japanese cypress pollinosis, it is closely associated with both the pathological and physiological severity of the pollinosis [22].

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Figure 4. Production of IL-31 by peripheral blood mononuclear cells in response to stimulation with a crude antigen extract of Japanese cypress pollen. (a) The cypress crude antigen extract-induced IL-5 production levels in control subjects (n = 8), Japanese cedar/cypress pollinosis (JCCP) patients without allergen-specific immunotherapy (ASIT) (n = 27) and JCCP patients with ASIT (n = 20) were compared. (b) The quality of life scores during the peak season of Japanese cypress pollen dispersion were compared between patients showing positive and negative production of IL-31 in response to the cypress crude antigen extract. The bars indicate the median values. The P values were determined using the Mann–Whitney U test.

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Effects of Japanese cedar pollen-specific immunotherapy on Japanese cypress pollinosis

Allergen-specific immunotherapy (ASIT) is an effective treatment for IgE-mediated Th2-biased allergic diseases, particularly AR [26]. Unlike pharmacotherapy, ASIT is unique in that it can alter the natural course of allergic disease by preventing new sensitization/onset and providing long-term remission after discontinuation of treatment [27-29]. In Japan, only a Japanese cedar pollen extract has been standardized, and a therapeutic extract of Japanese cypress pollen is not commercially available. Therefore, we generally use the standardized extract of Japanese cedar pollen for ASIT in JCCP patients.

Analyses using JRQLQ No. 1, as a Japanese QOL questionnaire for AR, indicated that ASIT with the standardized extract of Japanese cedar pollen is clinically effective for not only naso-ocular symptoms but also rhinitis-related QOL during the period of cedar pollen dispersion [30, 31]. On the other hand, the significant efficacy tends to be reduced in the late part of the season when Japanese cypress pollen is mainly dispersed (Fig. 5). This effect is remarkable when the dispersion of Japanese cypress pollen is high. For example, both naso-ocular symptoms and QOL worsened, even in patients with ASIT, during the cypress pollen season in 2006 when the annual dispersion of Japanese cypress pollen was approximately twice that of Japanese cedar pollen (Figs. 3 and 5) [32]. These findings suggest the existence of components that are unique to Japanese cypress pollen and do not cross-react with Japanese cedar pollen.

image

Figure 5. Effects of allergen-specific immunotherapy (ASIT) using a standardized extract of Japanese cedar pollen on naso-ocular symptoms and quality of life (QOL) in Japanese cedar/cypress pollinosis (JCCP). The naso-ocular symptoms (a, b) and rhinitis-related QOL (c, d) were compared between JCCP patients with ASIT (closed squares) and those without ASIT (open circles) during the pollen dispersion seasons in 2005 (a, c) and 2006 (b, d). The P values were determined using the Mann–Whitney U test.

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The amount of IL-5 produced by PBMCs in response to the crude antigen extract of Japanese cedar pollen was significantly lower in JCCP patients who received ASIT with the standardized extract of Japanese cedar pollen compared with those without ASIT (P < 0.001, Fig. 6a). On the other hand, although the IL-5 production in response to the crude antigen extract of Japanese cypress pollen was lower in JCCP patients who received ASIT than in those without ASIT, the difference was not statistically significant (P = 0.195, Fig. 6b). Interestingly, both Cry j 1- and Cha o 1-induced IL-5 production was significantly lower in JCCP patients with ASIT than in those without ASIT (Fig. 7). These findings suggest that unique component(s) other than Cha o 1 in Japanese cypress pollen can induce IL-5 production, which is not fully suppressed by ASIT with the standardized extract of Japanese cedar pollen. Identification of these unique component(s) and/or manufacture of a standardized extract of Japanese cypress pollen will be required to control Japanese cypress pollinosis through ASIT.

image

Figure 6. Comparison of the IL-5 production levels in response to a Japanese cedar crude antigen extract (a) and a Japanese cypress crude antigen extract (b) between peripheral blood mononuclear cells from Japanese cedar/cypress pollinosis patients with and without allergen-specific immunotherapy using a standardized Japanese cedar pollen extract. The P values were determined using Student's paired t-test.

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image

Figure 7. Comparison of the IL-5 production levels in response to Cry j 1 (a) and Cha o 1 (b) between peripheral blood mononuclear cells from Japanese cedar/cypress pollinosis patients with and without allergen-specific immunotherapy using a standardized Japanese cedar pollen extract. The P values were determined using Student's paired t-test.

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Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Characterization of Japanese cypress pollen
  5. Pathophysiology of Japanese cypress pollinosis
  6. Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis
  7. Conclusions
  8. Acknowledgments
  9. References

Early interventional treatment in the Practical Guideline for Management of Allergic Rhinitis in Japan

The initial pollen dispersion can cause a priming effect and a minimal persistent inflammation, which is characterized by the influx of inflammatory cells including eosinophils into the nasal mucosa. These conditions lead to hypersensitivity to allergens and non-specific irritants, and contribute to the onset of AR [1, 32]. Thus, the PG-MARJ recommends that patients who experience severe symptoms of pollinosis every year should receive early interventional treatment, i.e. prophylactic or initial treatment, immediately after the start of pollen release or the onset of symptoms [2]. Considering the amount of pollen release expected during the season and the type and severity of the symptoms usually experienced by patients during the peak pollen season, the PG-MARJ recommends that physicians should determine the drug regimen for individual patients by selecting from among chromones, second-generation H1RAs, LTRAs, a Th2 cytokine suppressor (suplatast) and a PGD2/TXA2 receptor antagonist (ramatroban) for early interventional treatment [2]. Evidence from studies using experimental animal models supports the efficacy of early interventional treatment for pollinosis [33, 34]. For example, we have revealed that early interventional treatment with ramatroban significantly suppresses sneezing, Cry j 1-specific IgG1 production and Cry 1-induced IL-4 production by submandibular lymph node cells, compared with a control treatment, in a murine model of Japanese cedar pollinosis [33].

Effects of early interventional treatment with a histamine H1 receptor antagonist on Japanese cedar/cypress pollinosis

The efficacy, limitations and safety of H1RAs for early interventional treatment in JCCP have been characterized. Two bases have arisen why second-generation H1RAs are suitable for early interventional treatment in pollinosis. First, H1RAs act as inverse agonists but not neutral antagonists [35]. As an inverse agonist combines with and stabilizes histamine H1 receptor (H1R) to shift the equilibrium towards the inactive state, even in the absence of histamine, use of an H1RA for early interventional treatment can suppress the priming effect and the minimal persistent inflammation, which can lead to a delay in the persistent onset of JCCP. Second, the gene expression of H1R is suppressed by H1RAs [36]. For example, the expression of H1R mRNA in the nasal mucosa during the peak pollen period was significantly lower in JCCP patients who received early interventional treatment with an H1RA compared with those without early interventional treatment [36]. Thus, early interventional treatment with H1RAs can suppress the induction of hyper-reactivity following exposure to pollen by reducing H1R expression.

One study involving a double-blinded placebo-controlled randomized trial showed that early interventional treatment with olopatadine hydrochloride significantly suppressed sneezing (P < 0.001), rhinorrhoea (P < 0.001), nasal congestion (P < 0.05) and impairment of QOL (P < 0.05) but not itching or watering of the eyes during the peak season of Japanese cedar pollen dispersion [7]. However, owing to the study period, the efficacy of this early interventional treatment on Japanese cypress pollinosis was not the intention of the investigation. A 3-year multicenter retrospective trial was performed to investigate the clinical efficacy of early interventional treatment with olopatadine hydrochloride in JCCP patients [37]. The trial revealed that the efficacy of olopatadine hydrochloride for early interventional treatment is dependent on the total amount of pollen dispersion during the season. In comparison with olopatadine hydrochloride treatment after the substantial onset of pollinosis, early interventional treatment with olopatadine hydrochloride was significantly effective throughout the study period, including the cypress pollen season, when the total amount of pollen dispersion was low (<2,000 grains/cm2). However, the significant efficacy of early interventional treatment was lost in the second half of the season, in which the Japanese cypress pollen is dispersed, when the total amount of pollen dispersion was extremely high (>5,000 grains/cm2) (Fig. 8c).

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Figure 8. Comparison of the naso-ocular symptom scores between patients who received early interventional treatment and those treated after the substantial onset of pollinosis. (a) The total pollen dispersion was lower than 2,000 grains/cm2, as determined by a Durham sampler. (b) The total pollen dispersion ranged from 2,001 to 5,000 grains/cm2. (c) The total pollen dispersion was higher than 5,000 grains/cm2.

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Similar results were seen in another large-scale non-randomized multicenter trial conducted in 2008 using epinastine hydrochloride for early interventional treatment. Using JRQLQ No. 2, the naso-ocular and non-naso-ocular symptoms were compared between patients with early interventional treatment (n = 1,079) and patients with treatment after the substantial onset of pollinosis (n = 1,678). In the 4 weeks after the onset of Japanese cedar pollen dispersion, when high dispersion of Japanese cedar pollen was seen, the patients who received early interventional treatment with epinastine displayed a significant alleviation in all naso-ocular symptoms (P < 0.001) and non-naso-ocular symptoms including cough (P = 0.020), hoarseness (P = 0.019), sore throat (P = 0.023), loss of smell (P = 0.003), dry mouth (P = 0.003), ear stiffness (P = 0.011), headache (P = 0.008) and snoring (P = 0.001), compared with those who received treatment after the substantial onset of pollinosis. On the other hand, in the 8 weeks after the onset of Japanese cedar pollen dispersion, when high dispersion of Japanese cypress pollen was seen, significant alleviation was only seen in rhinorrhoea (P = 0.002), nasal congestion (P = 0.001) and snoring (= 0.002) in the patients with early interventional treatment, and the rest of the domains did not differ significantly between the two groups. These findings suggest that, although early interventional treatment with an H1RA is effective for Japanese cedar pollinosis, especially at the beginning of the season, early interventional treatment has limitations for Japanese cypress pollinosis when the exposure to the pollen is high. Combined therapy with an LTRA and/or intranasal corticosteroids may be required to entirely control the worsening of JCCP during the cypress pollen season [38].

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Characterization of Japanese cypress pollen
  5. Pathophysiology of Japanese cypress pollinosis
  6. Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis
  7. Conclusions
  8. Acknowledgments
  9. References

Japanese cypress pollinosis has several unique characteristics. Since it has been suggested that the annual dispersion of Japanese cypress pollen will increase, better understanding of the pathogenesis of Japanese cypress pollinosis and the establishment of evidence-based therapy for Japanese cypress pollinosis are essential to fully control this ‘nationally detrimental’ seasonal AR.

Acknowledgments

  1. Top of page
  2. Summary
  3. Introduction
  4. Characterization of Japanese cypress pollen
  5. Pathophysiology of Japanese cypress pollinosis
  6. Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis
  7. Conclusions
  8. Acknowledgments
  9. References

The authors would like to thank Yohei Noda, Shin Kariya and Miki Yamamoto for their excellent help in editing this review. This work was supported in part by a grant for Research on Allergic Disease and Immunology from the Ministry of Health, Labour and Welfare, Japan (No. 23150301).

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Characterization of Japanese cypress pollen
  5. Pathophysiology of Japanese cypress pollinosis
  6. Effects of early interventional treatment with histamine H1 receptor antagonist on Japanese cypress pollinosis
  7. Conclusions
  8. Acknowledgments
  9. References