Immunotherapy For Japanese Cedar Pollinosis Research Articles

Sublingual Immunotherapy for Japanese Cedar Pollinosis: Current Clinical and Research Status.

The incidence of Japanese cedar pollinosis is increasing significantly in Japan, and a recent survey suggested that about 40% of the population will develop this disease. However, spontaneous remission is rare. The increased incident rate of Japanese cedar pollinosis is a huge issue in Japan. Allergen immunotherapy is the only fundamental treatment that modifies the natural course of allergic rhinitis and provides long-term remission that cannot be induced by general drug therapy. Sublingual immunotherapy for Japanese cedar pollinosis has been developed and has been covered by health insurance since 2014 in Japan. The indication for children was expanded in 2018. Clinical trials of sublingual immunotherapy for Japanese cedar pollinosis have demonstrated its long-term efficacy and safety. It is recommended for patients who wish to undergo fundamental treatment regardless of the severity of the practical guidelines for the management of allergic rhinitis in Japan. For sublingual immunotherapy, a long-term treatment period of 3 years or longer is recommended to obtain stable therapeutic effects. In recent years, evidence based on basic research and clinical trials has demonstrated sublingual immunotherapy-induced immunological changes and efficacy in patients; however, biomarkers that objectively predict and judge these therapeutic effects need to be established.

Complement Factor H Is an Early Predictive Biomarker of the Therapeutic Efficacy of Sublingual Immunotherapy for Japanese Cedar Pollinosis.

Sublingual immunotherapy for Japanese cedar pollinosis can improve the symptoms of allergic rhinitis and modify its natural course. However, sublingual immunotherapy requires a long treatment period and some patients do not respond to treatment. In this study, we aimed to identify biomarkers that could predict the efficacy of sublingual immunotherapy at an early stage. In this study, 40 patients from phase III trials were recruited and divided into good and poor response groups. Using peripheral blood mononuclear cells from before and two months after the start of medication, microarray, discriminant analysis, and real-time polymerase chain reaction were performed to extract candidate genes that could be biomarkers. Furthermore, these genes were validated in 30 patients in general clinical practice. Complement factor H was upregulated in the good response group and downregulated in the poor response group. Complement factor H may be a useful biomarker for predicting the efficacy of sublingual immunotherapy for Japanese cedar pollinosis at early time points after treatment initiation.

Predictors of adherence to sublingual immunotherapy for Japanese cedar pollinosis: a prospective analysis.

Sublingual immunotherapy (SLIT) often has low adherence rates. To provide effective support for SLIT continuation, we investigated potential predictors of SLIT adherence through a prospective analysis of patient characteristics. We excluded evaluation of treatment effect and symptoms during treatment, aiming instead to identify predictors of later dropout or insufficient adherence due to indolence or forgetfulness using only information obtained at initial examination. We provided patients with a questionnaire and monitored self-reported adherence once every 6 months. Cases of dropout for clear reasons were excluded, but cases of dropout or insufficient adherence to SLIT for indolence or forgetfulness were included. Fifty-three patients receiving SLIT were assessed. Nine patients dropped out after providing a clear reason. Thirty-four patients maintained good adherence. Seven patients continued SLIT but with insufficient adherence, while three patients discontinued SLIT for unclear reasons (indolence or forgetfulness) and these ten individuals were classified as the poor-adherence group. Univariate analysis and multivariate logistic regression analysis of the good-adherence and poor-adherence groups showed age to be a significant predictor of SLIT adherence. Based on analysis of a receiver operating characteristic curve, age < 40.5 years was selected as the optimal cutoff value for predicting poor adherence to SLIT. To prevent treatment SLIT discontinuation on account of indolence or forgetfulness, the necessity of longterm treatment continuity should be communicated clearly prior to commencing treatment, especially for patients under 40 years of age.

A case of Japanese cedar pollen allergy with throat itching and dyspnea by eating tomatoes during sublingual immunotherapy for Japanese cedar pollinosis

A case of Japanese cedar pollen allergy with throat itching and dyspnea by eating tomatoes during sublingual immunotherapy for Japanese cedar pollinosis

Decreased numbers of metachromatic cells in nasal swabs in Japanese cedar pollinosis following sublingual immunotherapy.

Background and ObjectiveNasal symptoms were reduced following allergen‐specific sublingual immunotherapy (SLIT) for allergic rhinitis. The mechanisms underlying the effectiveness of SLIT for Japanese cedar pollinosis are poorly understood. We studied changes in the numbers of metachromatic cells, eosinophils, and neutrophils following SLIT for Japanese cedar pollinosis.MethodsNasal swabs were taken in the preseason (n = 32) and in pollinosis season (n = 49) from subjects given sublingual drop immunotherapy for an average duration of 1.5 years. The numbers of metachromatic cells (mast cells and basophils), eosinophils and neutrophils were determined and compared with those from untreated subjects in preseason (n = 65) and in season (n = 54).ResultsSLIT subjects had a significantly reduced frequency of moderate to most severe symptoms in comparison to untreated subjects in preseason (P < .001, the Mann‐Whitney U test), and (P < .00001) in season. Metachromatic cell counts in nasal swabs of SLIT subjects in preseason and in season were lower than those of untreated subjects (P = .014, the Mann‐Whitney U test) and (P = .00001) respectively. Eosinophil numbers in SLIT subjects were not significantly different than in untreated subjects in both preseason (P = .29) and in season (P = .09). However, when SLIT subjects in season were divided into those with greater than or equal to 1.5 years, or <1.5 years of SLIT duration, the degree of eosinophilia in those with SLIT greater than or equal to 1.5 years was significantly lower (P = .011) than in untreated patients, but not in those with SLIT less than 1.5 years (P = .9). There were no significant differences in neutrophil numbers in nasal swabs between untreated and SLIT subjects in preseason and in season.ConclusionOne of mechanisms underlying the effectiveness of sublingual drop immunotherapy for Japanese cedar pollinosis is a reduction of the number of metachromatic cells in preseason and in season. Eosinophilia was also reduced in season in those given SLIT for greater than or equal to 1.5 years.

Allergen-specific subcutaneous immunotherapy for Japanese cedar pollinosis decreases the number of metachromatic cells and eosinophils in nasal swabs during the preseason and in season.

Background and objectiveNasal symptoms of allergic rhinitis can be reduced with allergen‐specific subcutaneous immunotherapy (SCIT). However, the mechanisms underlying the effectiveness of SCIT for Japanese cedar pollinosis are not well understood. We studied changes in the numbers of metachromatic cells, eosinophils and neutrophils in nasal swabs following SCIT for Japanese cedar pollinosis.MethodsSubjects were either untreated or given SCIT for 0.5 to 13 years duration. For the 2019 seasons, nasal swabs were taken in the pollinosis preseason (immunotherapy n = 36; untreated control, n = 62) and in the pollinosis season (immunotherapy n = 45; untreated control n = 46) and the numbers of mast cells, eosinophils and neutrophils assessed by microscopy.ResultsThere were significant improvements in symptom severities following SCIT in comparison to untreated subjects (P < .0003, the Mann‐Whitney U test) in preseason, and (P < .00001) in season. Metachromatic cell counts from nasal swabs of SCIT subjects in preseason and in the season were lower than those of untreated subjects (P = .0029 and P = .031, respectively). Eosinophil numbers in nasal swabs of subjects given SCIT were lower than in untreated subjects (P = .0031) in season, but not in preseason. There were no significant differences in degrees of neutrophilia between untreated and SCIT subjects in preseason and in season.ConclusionOne mechanism underlying the effectiveness of SCIT for Japanese cedar pollinosis involves a reduction in the number of metachromatic cells in nasal swabs in the preseason and an inhibition of increases in the number of metachromatic cells and eosinophils in season.

Solid-in-Oil Nanodispersions for Transcutaneous Immunotherapy of Japanese Cedar Pollinosis.

Japanese cedar pollinosis (JCP) is a common affliction caused by an allergic reaction to cedar pollen and is considered a disease of national importance in Japan. Antigen-specific immunotherapy (AIT) is the only available curative treatment for JCP. However, low compliance and persistence have been reported among patients subcutaneously or sublingually administered AIT comprising a conventional antigen derived from a pollen extract. To address these issues, many research studies have focused on developing a safer, simpler, and more effective AIT for JCP. Here, we review the novel antigens that have been developed for JCP AIT, discuss their different administration routes, and present the effects of anti-allergy treatment. Then, we describe a new form of AIT called transcutaneous immunotherapy (TCIT) and its solid-in-oil (S/O) nanodispersion formulation, which is a promising antigen delivery system. Finally, we discuss the applications of S/O nanodispersions for JCP TCIT. In this context, we predict that TCIT delivery by using a S/O nanodispersion loaded with novel antigens may offer an easier, safer, and more effective treatment option for JCP patients.

Preliminary Clinical Trial of Biomarkers to Predict Response to Sublingual Immunotherapy for Japanese Cedar Pollinosis.

As part of the planning for a future multicenter study, this preliminary clinical trial used serum samples from patients to identify biomarkers for predicting the therapeutic effects of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis (JCP). This prospective study included patients undergoing SLIT for JCP at our hospital. All enrolled patients (N = 17) started SLIT between June and November of 2015. With informed consent from the patients, blood samples were obtained in January, March, and June of 2016, and patients completed the Japan rhino-conjunctivitis quality of life questionnaire (JRQLQ). On the basis of the JRQLQ results, the 6 patients with the best outcomes were included in the high-response group (HRG), and the 5 patients with the worst outcomes were included in the poor-response group (PRG). We then compared serum data between the two groups, to identify useful biomarkers. IL-12p70 and VEGF levels tended to be higher in the HRG than in the PRG in January, March, and June (0.10 > p > 0.05). In addition, the June IL-17 level was significantly higher (p < 0.05) in the HRG than in the PRG. IL-12p70 and VEGF may be useful biomarkers for predicting the effects of SLIT. In addition, although IL-17 does not appear to be useful as a biomarker for evaluating treatment response at the start of SLIT, it may be useful as a biomarker after the beginning phase of SLIT.

Serum Cytokine Interactions Are Implicated in the Mechanism of Action of Sublingual Immunotherapy for Japanese Cedar Pollinosis.

This study aimed to investigate whether interactions between multiple serum cytokines may be implicated in the mechanism of action (MOA) of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. A Tokyo Metropolitan Bureau of Social Welfare and Public Health-initiated clinical study of active SLIT involving 202 patients with Japanese cedar pollinosis was jointly conducted by Tokyo Metropolitan Institute of Medical Science and Nippon Medical School between 2006 and 2008. Fifty target cytokines were quantified in serum samples collected at 6 times from baseline to the end of the study, for 300 cytokine measurements in total, using Bio-Plex Pro Human Cytokine Group I/II Panels. Therapeutic outcome was assessed based on nasal symptom scores and quality-of-life questionnaire results. Fifty-five percent of patients were free of symptoms or reported symptomatic improvements by 2 grades or greater after 2 years of SLIT treatment, while 27% showed no improvement or worsening of symptoms. Thirty-eight patients who benefited the most from treatment (responders) as well as 37 patients who benefited the least from treatment (non-responders) were identified and their serum cytokine profiles were compared. Cluster analysis of the 300 cytokine measurements identified 6 cytokine clusters that were strongly correlated with a positive response to treatment, and this correlation was consistent throughout the treatment. Certain cytokine clusters are strongly correlated with a positive therapeutic outcome, suggesting they have a role in the MOA of immunotherapy.

Sublingual immunotherapy for Japanese cedar pollinosis: potential biomarkers predicting therapeutic responses

Sublingual immunotherapy for Japanese cedar pollinosis: potential biomarkers predicting therapeutic responses

T helper 1 (T&lt;sub&gt;H&lt;/sub&gt;1), Th2, and Th17 cytokine-profiles during long-term sublingual immunotherapy for Japanese cedar pollinosis

T helper 1 (T&lt;sub&gt;H&lt;/sub&gt;1), Th2, and Th17 cytokine-profiles during long-term sublingual immunotherapy for Japanese cedar pollinosis

小児におけるスギ皮下急速免疫療法の有効性と安全性の検討

小児におけるスギ皮下急速免疫療法の有効性と安全性の検討

スギ舌下免疫療法初回投与後に生じたアナフィラキシーの1例

標準化スギ花粉エキス（シダトレン®）を用いた舌下免疫療法（sublingual immunotherapy: SLIT）の初回投与後に副反応を生じた症例を報告する。46歳女性。主訴は鼻汁，鼻閉。既往歴に食物アレルギー，気管支喘息（最近5年間発作なく呼吸機能正常），慢性副鼻腔炎（術後）があった。SLITの適応は，当院のリウマチ・膠原病内科および皮膚科コンサルトして慎重に決定した。スギ花粉非飛散期に入院して副反応に対する準備の上SLIT導入した。初回投与日の全身状態は良好であった。規定のプロトコール通り，シダトレン®（40 JAU/0.2 mL）を医師が初回投与した。アレルゲン曝露2～5分後に，皮膚・粘膜症状（頸部～頬部），消化器症状（口腔咽喉頭違和感），呼吸器症状（息苦しさ），循環器症状（血圧低下）を呈した。意識障害はなかった。過去に経験した食物アレルギーに伴うアナフィラキシーよりも軽度であったが，これらの反応はアナフィラキシー（グレード3）と考えられた。水うがい，β2受容体刺激薬吸入を行い，アレルゲン曝露の30分後にはこれらの症状は消失した。増量期は入院してプロトコール通りの投与量で行った。2日目以降は，アナフィラキシー反応は認めなかった。維持期となり退院した。SLIT開始から1年経過した現在，副反応を認めず維持療法を継続中である。アレルギー疾患合併症例においては，SLITの導入は慎重な判断と副反応に対する厳重な監督下で行う必要があると考えられた。

Transcutaneous Peptide Immunotherapy of Japanese Cedar Pollinosis Using Solid-in-Oil Nanodispersion Technology.

Peptide immunotherapy is an attractive approach to relieve allergic symptoms such as rhinitis and asthma. Treatment of Japanese cedar pollinosis (Cryptomeria japonica; Cj), from which over one quarter of Japanese population suffer, is becoming a great concern. Recently, oral feeding of a peptide (7crp) consisting of seven immunodominant human T cell epitopes derived from two enzymes present in Cj pollen was demonstrated to have a benefit in treating Cj pollinosis. In this work, we aimed to apply a novel transcutaneous administration system as a simple and easy peptide delivery for an immunotherapy using a T cell epitope peptide. A modified 7crp peptide (7crpR) which contained triarginine linkers between each epitopes was designed to increase water solubility and was encapsulated in a unique solid-in-oil (S/O) nanodispersion. The S/O nanodispersion consists of a nano-sized peptide-surfactant complex dispersed in an oil vehicle. The S/O nanopartilces having an average diameter of 230 nm facilitated the permeation of the peptide 7crpR into the skin and suppressed serum total IgE and antigen-specific IgE levels in a Cj pollinosis mouse model. Transcutaneous administration of the T cell epitope peptide using the S/O nanodispersion system has potential for future simple and easy immunotherapy of Cj pollinosis.

Long-term sublingual immunotherapy for Japanese cedar pollinosis and the levels of IL-17A and complement components 3a and 5a

Allergen-specific immunotherapy is the only treatment that can alter the natural course of allergic disease. We performed long-term sublingual immunotherapy (SLIT) for patients with seasonal allergic rhinitis caused by Japanese cedar pollen (SAR-JCP), screened molecules as candidate biomarkers, and investigated serum IL-17A and complement components 3a (C3a) and C5a in order to evaluate whether these molecules show changes correlated to symptom scores. In this study, we found that the long-term SLIT reduced the serum levels of IL-17A and C3a and C5a. The levels of C3a in the patients significantly decreased from year 1 compared with those at the baseline, and their levels of IL-17A significantly decreased from year 2 compared with those at baseline. The levels of IL-17A, C3a, and C5a at year 4 of SLIT were significantly lower than not only those at baseline, but also those at year 1. A significant positive correlation was found between the symptom medication scores and the levels of IL-17A at year 4. The symptom medication scores in the group in which IL-17A levels decreased at year 4 were significantly lower than those in the group without such a decrease. The serum level of IL-17A might prove useful as a biological parameter to ascertain the effectiveness of SLIT for patients with SAR-JCP. It is necessary to produce new therapeutics for non-responders in whom serum IL-17A levels are still higher against long-term SLIT.

Effectiveness of Subcutaneous Immunotherapy for Japanese Cedar Pollinosis

Initial drug therapy is effective in Japanese cedar pollinosis. However, some patients cannot take medications because they are ineffective, undesirable or have serious side effects. These patients choose treatments such as immunotherapy or surgical intervention. Although allergic rhinitis is not lethal, it can decrease the quality of life (QOL) with sudden short-term aggravation, such as that caused by Japanese cedar pollinosis. To assess allergic rhinitis therapy objectively, we studied the difference in the effects of subcutaneous immunotherapy (SCIT) and initial drug therapy using a visual analogue scale (VAS) to assess symptoms and a QOL questionnaire. This study enrolled patients who were examined during the cedar pollen season in 2011 and divided them into three groups: the immunotherapy, initial drug therapy, and after onset groups. The results showed that SCIT had marked effects on symptoms such as sneezing, nasal discharge, eye itching, and lacrimation via an antihistaminic action and improved the QOL, including daily life, outdoor activities, and spiritual life during the pollen season. Due to its efficacy for both treatment of the symptoms and improvement of the QOL of our patients, we plan to continue to promote SCIT.

Effectiveness of Subcutaneous Immunotherapy for Japanese Cedar Pollinosis

Effectiveness of Subcutaneous Immunotherapy for Japanese Cedar Pollinosis

Sublingual immunotherapy for Japanese cedar pollinosis: current status in Japan

SummaryImmunotherapy is not generally used in Japan and very few medical institutions perform it. For radical treatment, immunotherapy should be selected. However, subcutaneous immunotherapy has not yet gained acceptance. Japanese cedar pollinosis is a seasonal allergic rhinitis that is indigenous to Japan and occurs with a nationwide mean prevalence of 25%. Clinical research on sublingual immunotherapy for Japanese cedar pollinosis has made progress and it should come into practical use within 2–3 years. If sublingual immunotherapy becomes practical, it should provide a new treatment option for Japanese cedar pollinosis.

Therapeutic outcomes and immunological effects of sublingual immunotherapy for Japanese cedar pollinosis

SummaryIn Japan, about a quarter of the population has Japanese cedar pollinosis. One promising treatment is sublingual immunotherapy, which is under clinical investigation in Japan and not yet covered by the national health insurance system. Since 2005, we have treated more than 200 patients with Japanese cedar pollinosis. We found that sublingual immunotherapy is more effective than drug treatment, but less effective than subcutaneous immunotherapy. Moreover, patients receiving sublingual immunotherapy or subcutaneous immunotherapy use fewer concomitant medications than patients receiving drug treatment. Therefore, sublingual immunotherapy seems to be effective and associated with decreased drug use. The effect of sublingual immunotherapy seems to increase with increasing duration of treatment; the treatment seems to be more effective when continued for ≥4 years than when discontinued after 3 years. We aimed to elucidate the mechanism of action of sublingual immunotherapy. We found that sublingual immunotherapy increases the percentage of interleukin (IL)‐10–producing inducible regulatory T cells, and that IL‐10 is involved in the immune response to Japanese cedar pollen. Furthermore, levels of antigen‐specific immunoglobulin G4 are increased in the cedar pollen season in patients receiving sublingual immunotherapy, and serum levels of IL‐33 are increased in non‐responders. Our findings should contribute to the further development of sublingual immunotherapy for Japanese cedar pollinosis.

389 Allergen specific immunotherapy for Japanese cedar pollinosis

389 Allergen specific immunotherapy for Japanese cedar pollinosis