Increase in the prevalence of follicular regulatory T cells correlates with clinical efficacy of sublingual immunotherapy with house dust mites.

BACKGROUND: Allergic rhinitis (AR) impairs quality of life and affects nearly 40% of the Japanese population. Sublingual immunotherapy (SLIT) is the disease-modifying treatment for AR, but requires the selection of a biomarker associate with clinical efficacy in patients with AR who are treated with SLIT. The present study sought to examine objective biomarkers used for assessing the clinical efficacy of SLIT. METHODS: The authors examined the effects of 1 year of SLIT treatment with house dust mites (HDMs) using peripheral blood mononuclear cells (PBMCs) and serum from patients with AR. The prevalences of follicular regulatory T (Tfr), type 2 follicular helper T (Tfh2), type 2 helper T (Th2), conventional regulatory T (Treg), and type 1 regulatory T (Tr1) cells were examined by flow cytometry. Serum concentrations of HDM-specific IgA, IgE, and IgG4 antibodies, and HDM-induced production of interleukin (IL) 5 and IL-10 from cultured PBMCs were evaluated by enzyme-linked immunosorbent assay. RESULTS: Following 1 year of SLIT, the prevalences of Tfr, conventional Treg, and Tr1 cells were significantly increased, whereas that of Th2 cells and Tfh2 cells were significantly decreased; the serum concentration of HDM-specific IgG4 was significantly increased; and HDM-induced production of IL-5 from PBMCs was significantly decreased, while that of IL-10 was significantly increased. The increase in the prevalence of Tfr cells after SLIT correlated positively with the improvement of clinical symptom scores. CONCLUSION: An increase in Tfr cells may play an important role in SLIT, and may be a useful indicator for the clinical efficacy of SLIT.

[CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY WITH CEDAR POLLEN IN A YEAR OF MASSIVE CEDAR POLLEN DISPERSAL AND ITS EFFECT ON JAPANESE CYPRESS POLLINOSIS].

BACKGROUND: We investigated the effect of sublingual immunotherapy (SLIT) on Japanese cedar and cypress pollinosis in a mass scattering year of cedar pollen (total counts: 12353 grains/cm2, approximately four times the average). METHODS: SLIT patients of 84 in the first year, 107 in the second year and 67 in the third year treated with Cedarcure® were included. During the 2023 cedar and cypress pollen dispersal season, nasal and eye symptoms and general symptoms were examined using a visual analog scale (VAS). RESULTS: The VAS during the cedar season significantly decreased to improve with the number of years of SLIT, but the VAS during the cypress period slightly increased. A questionnaire survey before SLIT revealed that only 0.9% to 3.6% of patients had strong cypress symptoms. However, sneezing (p＜0.01), rhinorrhea, itchy eyes and total symptoms (p＜0.05) in the third year of SLIT were significantly stronger during the cypress period than during the cedar period. The VAS of total symptoms during the Japanese cedar pollen season were not affected by the pollen count, and the cure rate was affected by SLIT in the third year. CONCLUSION: The clinical efficacy of cedar SLIT on cedar pollinosis was high even in a mass scattering year, and the effect increased with the number of years of treatment. On the other hand, it was shown that the clinical efficacy on cypress pollinosis was insufficient.

[A MULTICENTER CLINICAL SURVEY ABOUT THE PREVALENCE OF JAPANESE CYPRESS POLLINOSIS AND THE EFFICACY OF SUBLINGUAL IMMUNOTHERAPY WITH JAPANESE CEDAR POLLEN EXTRACT DURING JAPANESE CYPRESS POLLEN DISPERSAL PERIOD].

BACKGROUND: Little is known whether sublingual immunotherapy using Japanese cedar pollen extract (cedar SLIT) is effective for not only Japanese cedar pollinosis but also Japanese cypress pollinosis. We investigated the prevalence rate of Japanese cypress pollinosis, efficacy of cedar SLIT on cypress pollinosis and patients' wish to receive cypress SLIT. METHODS: We investigated a multi-center (31 institutions), cross-sectional survey using a self-administrated questionnaire with four questions for patients received cedar SLIT aged from 5 to 69 years old. RESULTS: 2523 subjects were enrolled for analysis. 83.4% of them had pollinosis symptoms during cypress season before cedar SLIT. In such patients, 37.4% experienced lessened efficacy of cedar SLIT during cypress season. Both the prevalence of cypress pollinosis and the lessened efficacy of cedar SLIT on cypress pollinosis were significantly seen in western Japan as compared to eastern Japan. 76.1% of the subject having cypress pollinosis before SLIT wished to receive cypress SLIT if it is available. CONCLUSION: A lessened efficacy of cedar SLIT during cypress season was broadly seen in Japan, and further showed a regional difference. Together with the finding of high wish by patients, these results suggest a development of cypress SLIT is desirable.

[CLINICAL EFFICASY OF HOUSE DUST MITE SUBLINGUAL IMMUNOTHERAPY WITH MITICURE® TABLETS IN 115 PAITENTS FOR 3 YEARS].

We reported the results of three years of house dust mite sublingual immunotherapy with Miticure® tablets. METHODS: Subjects of 115 cases (63 males, median 12.9 years old, 74 children under 15 years old) were evaluated with Japanese Rhino-conjunctivitis Quality of Life Questionnaire No1 (JRQLQ No1) and visual analog scale (VAS) of 100mm length for rhino-ocular and general symptoms. Annual survey was conducted for three years. RESULTS: Symptoms in all items of 1 to 3 years later by JRQLQ No1 and VAS were significantly improved (p<0.01). There was no difference from 1 year to 3 years later. The VAS value for total symptoms decreased from 41 (18-70) mm before treatment to 10 (4-40) mm after 1 year and 10 (3-30) mm after 3 years (median (IQR)). Concomitant medications used in all patients at the start of treatment were not needed in 60.8% after 1 year and 65.2% after 3 years. After 3 years, 16.5% of the patients were completely cured with no concomitant medication and had a symptom score of 0, and 53.0% were in remission with a score of 1 or less. There was no difference in all items between children and adults, and symptoms improved equally. CONCLUSION: The efficacy of house dust mite sublingual immunotherapy from 1 to 3 years was demonstrated.

[ENHANCED CLINICAL EFFECTS OF CEDARCURE® TABLETS OF SUBLINGUAL IMMUNOTHERAPY OVER THE YEARS OF TREATMENT AND THE IMPACT OF OUTCOME BY COMBINED USE OF MITE SUBLINGUAL IMMUNOTHERAPY (DUAL SLIT) FOR JAPANESE CEDAR POLLINOSIS].

BACKGROUND: We examined the clinical effects of Cedarcure® tablets for sublingual immunotherapy (SLIT), and examined the enhancement of the effects over the years of treatment. METHODS: The subjects were 358 patients who treated with SLIT (126 of third year of treatment, 102 of second year, 130 of first year) in a single clinic. The clinical efficacy was evaluated with visual analog scale (VAS) of nose, eye and total symptoms during the peak season of moderate amount of pollen dispersal (2485 grains/cm2/season) in 2022. Concomitant medication scores were calculated by Japanese guidelines. Because many cases of combined use of mite SLIT (dual SLIT) were included in the subjects, we compared cedar SLIT alone and dual SLIT as a secondary analysis. RESULTS: Clinical efficacy improved with the years of treatment, and all assessments of VAS in the 3rd year were significantly better than in the 1st year of treatment (p<0.01). The third year was better with sneezing and nasal discharge than the 2nd year, and the 2nd year was better with itchy eyes than the 1st year (p<0.05). Drug scores were also lower in the 3rd and 2nd years than in the 1st year (p<0.05). Additional mite SLIT did not affect the results. CONCLUSION: Cedarcure® showed enhancement of the effects over the years of treatment by the analysis up to the third year. Both Cedar SLIT alone and Dual SLIT showed similar efficacy on cedar pollinosis.

Anti-inflammatory roles of interleukin-35 in the pathogenesis of Japanese cedar pollinosis.

BACKGROUND: Interleukin (IL)-35 has been recently identified as an anti-inflammatory cytokine in allergic inflammation. However, its biological role in the pathogenesis of allergic rhinitis has not been fully elucidated. OBJECTIVE: The purpose of this study was to investigate the anti-inflammatory activity of IL-35 in the pathogenesis of allergic rhinitis in patients with Japanese cedar pollinosis (JCP). METHODS: Peripheral blood mononuclear cells were collected from healthy controls and JCP patients during the off-season for pollen. Peripheral blood mononuclear cells were incubated with Cry j 1, a major allergen of Japanese cedar pollen and production of IL-5, IL-13, and IL-35 were measured by enzyme-linked immunosorbent assay. Th2 (CD4+ST2+) cells and group 2 innate lymphoid cells were isolated from peripheral blood mononuclear cells of JCP patients, and the inhibitory effects of IL-35 on cell differentiation, proliferation and mRNA expression of IL-5, IL-13, and GATA3 were examined. B cells were also isolated and the effects of IL-35 on total IgE production were examined. RESULTS: Cry j 1-induced production of IL-5 and IL-13 was significantly increased in peripheral blood mononuclear cells from JCP patients, whereas Cry j 1-induced IL-35 production was significantly decreased compared with healthy controls. IL-35 significantly inhibited Th2 cell differentiation, group 2 innate lymphoid cell proliferation, and mRNA expression of IL-5, IL-13, and GATA3 in Th2 cells and group 2 innate lymphoid cells. IL-35 also inhibited IgE production from B cells. CONCLUSION: IL-35 is an important anti-inflammatory cytokine in JCP, and its biological roles include the downregulation of Th2 cells and group 2 innate lymphoid cells, and the inhibition of IgE production from B cells. These findings demonstrate that IL-35 may have the potential to exert anti-allergic effects for the treatment of allergic rhinitis.

[COMPARISON OF CLINICAL EFFICACY AND SAFETY BETWEEN CHILDREN AND ADULTS BEFORE AND 1 YEAR AFTER MITE SUBLINGUAL IMMUNOTHERAPY FOR PERENNIAL ALLERGIC RHINITIS].

BACKGROUND: We studied clinical efficacy and safety after 1 year of mite sublingual immunotherapy (SLIT) for perennial allergic rhinitis in children, compared with adults. METHODS: We compared 121 children under 15 yeas old (81 male, aged 5-14 years, a median of 12 years) and 77 adults (36 male, aged 15-65 years, a median of 26 years) treated with mite SLIT tablet (10000 Japanese Allergy Unit). The clinical efficacy before and 1 year after SLIT was evaluated by assessing symptom scores by Japanese rhino-conjunctivitis quality of life questionnaire (JRQLQ No1) and visual analog scale (VAS). Combined medication was also compared. Adverse events of SLIT were checked at every visit. RESULTS: All items of JRQLQ No1 scores and VAS after 1 year of mite SLIT, except eye symptoms in adults by JRQLQ No1, were significantly improved in both children and adults. Comparing children and adults, there were no differences in symptoms before and after 1 year. Combined medication score showed a similar result. Adverse events were observed in 57.9% of children and 58.4% of adults, but there were no serious adverse reactions. CONCLUSION: There was no difference between children and adults in efficacy and safety of mite SLIT, and both group showed significant improvement of symptoms.

[EFFICACY AND SAFETY OF PEDIATRIC SUBLINGUAL IMMMUNOTHERAPY WITH CEDARCURE® IN CLINICAL PRACTICE FOR JAPANESE CEDAR POLLINOSIS IN THE FIRST FOLLOW-UP SEASON].

BACKGROUND: We studied clinical efficacy and safety of pediatric sublingual immunotherapy of cedar pollinosis in the first follow-up year, compared with adult cases or untreated cases. METHODS: We compared 103 pediatrics under 15 yeas old (age, 10.8±2.6 years; male-to-female ratio, 68;35) and 89 adults (age, 38.9±12.5 years; male-to-female ratio, 34;55) treated with Cidarcure®, and untreated 299 patients (age, 31.3±16.0; male-to-female ratio, 144;155). The clinical efficacy was evaluated by assessing symptom scores by Japanese rhino-conjunctivitis quality of life questionnaire and visual analog scale (VAS) during the peak season of moderate amount of pollen dispersal (3582 grains/cm2/season) in 2020. Adverse events of sublingual immunotherapy were also checked at every visits. RESULTS: All patients in both pediatric and adult group successfully maintained the highest dose of 5000JAU as planned. Pediatrics compared with adults showed slightly better effects in all the assessments, but they were not significant. Both pediatrics and adults of sublingual immunotherapy showed significant better effects in all the assessments compared with untreated group. Percentage of total cases of adverse events in pediatric group was low, but it was not significant. Percentage of pruritus of ear and throat was significantly low in pediatric group. CONCLUSION: Pediatric sublingual immunotherapy for cedar pollinosis was treated in safe, and reduced symptoms as well as the effects of adults.

Safety profile and immunological response of dual sublingual immunotherapy with house dust mite tablet and Japanese cedar pollen tablet.

BACKGROUND: There have been no studies of dual administration of sublingual immunotherapy (SLIT) tablets for perennial and seasonal allergic rhinitis. This trial (JapicCTI-184014) was conducted to investigate the safety profile and immunological response during dual therapy with SQ house dust mite (HDM) and Japanese cedar pollen (JCP) SLIT tablets. METHODS: This was a multicenter, open-label, randomized trial of 109 Japanese patients with coexisting HDM and JCP allergic rhinitis who had positive tests for HDM- and JCP specific IgE (≥0.7 kU/L). Patients were allocated to receive HDM (N = 54) or JCP (N = 55) SLIT tablets alone for 4 weeks followed by 8 weeks of dual therapy with both SLIT tablets administered within 5 min of each other. Adverse events (AEs), adverse drug reactions (ADRs), and serum IgE and IgG4 specific for HDM (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and JCP were recorded. RESULTS: The percentage of subjects with AEs and ADRs was similar between the two groups and between the two periods of monotherapy and dual therapy. Most AEs and ADRs were mild in severity, and no serious events were observed. The most common ADRs were local events in the oral cavity. Levels of IgE and IgG4 specific for HDM (D. farinae, D. pteronyssinus) and JCP were increased after treatment with HDM and JCP SLIT tablets, respectively. CONCLUSIONS: Dual therapy with both SLIT tablets administered within 5 min after 4 weeks of monotherapy with HDM or JCP tablet was well tolerated and induced the expected immunological responses.

Immunological effects of sublingual immunotherapy with Japanese cedar pollen extract in patients with combined Japanese cedar and Japanese cypress pollinosis.

Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis.

[CLINICAL EFFICACY OF 69 PATIENTS WITH JAPANESE CEDAR POLLINOSIS TREATED BY SUBLINGUAL IMMUNOTHERAPY WITH CEDARCURE® IN THE FIRST FOLLOW-UP YEAR].

BACKGROUND: Cedarcure® for sublingual immunotherapy of cedar pollinosis was purchased in 2018. We studied clinical efficacy of Cedarcure® in the first year. METHODS: We compared 69 patients treated with Cedarcure® (age, 18.0±13.5 years; male-to-female ratio, 40;29) and a control group of 97 patients treated with Cedartolen® (age, 29.8±16.2 years; male-to-female ratio, 44;53) during the peak season of large amount of pollen dispersal (10933 grains/cm2/season) in 2019. The clinical efficacy was evaluated by assessing symptom scores by Japanese rhino-conjunctivitis quality of life questionnaire and visual analog scale (VAS). RESULTS: All the assessments except nasal congestion were slightly better in Cedarcure® group, but they were not significant. There was no difference of concomitant medication in both groups. Because insurance coverage of Cedartolen® is for patients over 12 years old in Japan, the efficacy in Cedarcure® group enhanced better in all assessments if comparing the patients of over 12 years old. Percentage of adverse events was even in both over and under 12 years old. CONCLUSION: Cedarcure® was treated in safe, and reduced symptoms as well as Cedartolen®.

Role of whole saliva in the efficacy of sublingual immunotherapy in seasonal allergic rhinitis.

BACKGROUND: The development of methods to predict the clinical effectiveness of sublingual immunotherapy (SLIT) for allergic diseases is a crucial matter. We sought to determine whether whole saliva, which is the first body component that contacts allergen extracts during SLIT, is associated with the clinical effectiveness of SLIT in Japanese cedar pollinosis. METHODS: Blood monocytes or monocytic THP-1 cells were cultured in the presence or absence of either whole saliva or pure saliva with or without treatments including filtration and blockade of TLR2 and/or TLR4 signaling. IL-10 levels in the supernatants were then measured. Whole saliva-induced IL-10 production by THP-1 cells was compared between asymptomatic and disease-onset patients during peak pollen dispersal after SLIT. RESULTS: Both monocytes and THP-1 cells produced substantial amounts of IL-10 in response to whole saliva. IL-10 production was significantly reduced in response to pure saliva and 0.2 µm-filtered saliva. Simultaneous treatment with polymyxin B and TL2.1, a neutralizing antibody against TLR2, also reduced IL-10 production. IL-10 levels produced by THP-1 cells in response to whole saliva collected prior to SLIT were significantly higher in asymptomatic patients determined by symptom-medication scores than disease-onset patients following SLIT. Such differences were not seen in saliva collected 3 months after the initiation of SLIT or saliva collected during peak pollen dispersal. CONCLUSIONS: Our results provide a basis for why the sublingual route is effective and preferable in allergen immunotherapy. Saliva-induced IL-10 levels produced by THP-1 cells may be a predictive marker for clinical remission after SLIT.

[CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY IN A LARGE AMOUNT OF POLLEN DISPARSAL AND IT'S IMPACT OF TREATMENT YEAR].

BACKGROUND: It past 4 years in 2018 after the first treatment of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. The purpose of this study is to clear the clinical efficacy of SLIT in a large amount of pollen dispersal in 2018 (total 5041 grain). METHODS: The subjects were 270 SLIT (83 forth year of treatment, 72 third year, 48 second year, 67 first year), 320 primary pharmacotherapy that started therapies before pollen dispersal, and 424 untreated. The clinical efficacy was evaluated with symptom scores of Japanese rhinoconjuctivitis quality of life questionnaire No1, medication scores and combined total nasal symptom-medication scores, and visual analog scale of nose, eye and total symptoms. RESULTS: Each SLIT was significantly better than untreated in all assessments, and better than primary pharmacotherapy in assessments of total symptom. SLITs of third and forth year of treatment were also better than primary pharmacotherapy in nasal symptoms. SLIT patients, whose symptom scores of nose and eye were 0 and 1 point without any rescue drugs, accounted for 41.0%, 31.9%, 18.8%, 20.9% in the order from the fourth year to the first year. Of them, patients with score 0 occupied 12.0%, 12.5%, 4.2%, 4.5%, in order. There was no patient who needs treatments for adverse events. CONCLUSION: SLIT was significantly effective compared with primary pharmacotherapy or untreated group in a large amount of pollen dispersal. It was better to treat at least for 4 years.

[CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY IN THE THIRD TREATED YEAR WITH JAPANESE CEDAR POLLINOSIS IN 2017].

It past 3 years in 2017 after the first purchase of the drug for sublingual immunotherapy (SLIT) for Japanese Cedar pollinosis (JCP). We reported the clinical efficacy of SLIT in the first and the second treated year. PURPOSE: The purpose of this study is to clear the clinical efficacy of SLIT in the third treated year by comparing with other therapies, such as subcutaneous immunotherapy (SCIT), or other pharmacotherapy. METHODS: We compared the clinical efficacy in 2017, of 112 SLIT in the third treated year with 38 SCIT, 364 primary pharmacotherapy that started therapies before pollen dispersal, 254 pharmacotherapy that started therapies after pollen disposal, or 333 non-treatment. The clinical efficacy was evaluated with symptom scores, total nasal symptom scores and combined total nasal symptom-medication scores (TNSMS), symptoms of nose and eye by visual analog scale (VAS), quality of life (QOL) scores by Japanese rhino-conjunctivitis QOL questionnaire (JRQLQ No1). RESULTS: Both SCIT and SLIT showed good clinical efficacy without significant difference in every assessment. Both SCIT and SLIT were significantly better than other pharmacotherapy in most assessment. Patients, whose symptom scores of nose and eye were 0 and 1 point without any rescue drugs, accounted for 9 and 24% of total SLIT, respectively. CONCLUSION: SLIT in the third treated year showed good clinical efficacy in reducing symptoms and TNSMS of JCP, and in improving QOL. SLIT was significantly effective compared with other pharmacotherapies.