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Background Immediate- and late-phase reactions are associated with nasal symptoms of patients with allergic rhinitis. Objective To examine the symptoms and mediators released after continuous allergen exposure in an environmental challenge chamber (ECC). Methods Fifteen patients with Japanese cedar pollinosis were enrolled in this study and continuously exposed to cedar pollen at a concentration of 8,000 grains/m 3 for 3 hours in an ECC. Nasal function tests were performed, and nasal secretions were collected before pollen exposure (0 hour), immediately after exiting the ECC (3 hours), and 6 hours after exiting the ECC (9 hours). Symptom scores were recorded every 30 minutes in the ECC and every 3 hours after exiting the ECC. The frequency of sneezing and nose blowing also was monitored. Results The severity of symptoms in the ECC peaked approximately 2 hours after the beginning of pollen exposure and continued more than 6 hours after leaving the ECC. Concentrations of histamine, tryptase, interleukins 5, 3, 33, and 31, and substance P increased over time, whereas that of nasal fractional exhaled nitric oxide decreased. Conclusion Various mediators are released during continuous allergen exposure, which subsequently induce persistent nasal symptoms. Effective treatment is required to control the intense inflammation observed after allergen exposure.

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease of uncertain pathogenesis. Memory T cells acquire additional functions during the secondary response and play important roles in chronic inflammation. Objective To investigate characteristics of tissue memory CD4 + T cells obtained from patients with noneosinophilic CRSwNP (NECRS) and eosinophilic CRSwNP (ECRS) by focusing on the influence of interleukin (IL)-25. Methods Pro-allergic cytokines in tissue homogenates were measured using enzyme-linked immunosorbent assays. NP mononuclear cells and CD4 + T cells were isolated from NPs from patients with CRSwNP. Cytokine expression and CD4 + T-cell subpopulations were analyzed using enzyme-linked immunosorbent assay, flow cytometry, and real-time polymerase chain reaction. Results The IL-25 level in NPs increased in patients with ECRS. IL-5 and IL-9 mRNA levels expressed by tissue CD4 + T cells were significantly elevated in patients with ECRS. Most infiltrating CD4 + T cells in ECRS and NECRS expressed CD45RO; however, regardless of the atopic status, high IL-17RB levels were detected in CD4 + T cells from patients with ECRS. IL-17RB mRNA levels expressed by tissue CD4 + T cells significantly correlated with the number of eosinophils in NPs. Elevation of IL-5 and IL-9 production was found in NP mononuclear cells from patients with ECRS, but not in those from patients with NECRS, by stimulation with IL-25 under T-cell receptor stimulation. Conclusion Interleukin-25 and a subpopulation of tissue T-helper type 2 and 9 cells that express increased IL-17RB levels could contribute to infiltration of eosinophils in NPs and could have produced the pathologic difference between NECRS and ECRS.

Background: The efficacy of prophylactic treatment before the start of pollen dispersal for prevention of aggravation of symptoms is unclear. The aim of the present study was to examine the efficacy of prophylactic treatment with an antihistamine for seasonal allergic rhinitis (SAR) using an environmental challenge chamber (ECC). Methods: The study was performed in a randomized double-blind manner with a 3-way crossover design. The subjects were 50 patients with SAR caused by Japanese cedar pollen who were randomized for treatment with levocetirizine hydrochloride 5 mg (Xyzal®) or placebo as follows: administration of placebo for 8 days (treatment A), single administration of levocetirizine on day 8 after placebo for 7 days (treatment B) or administration of levocetirizine for 8 days (treatment C). Efficacy in each treatment arm was evaluated based on cedar pollen exposure for 3 h on day 9 in an ECC, following 1-hour exposure on day 8. The primary endpoint was the total nasal symptom score for 12 h on day 9. Other nasal and ocular symptoms were secondary endpoints. Results: The evaluation was performed in 45 subjects. The total nasal symptom score on day 9 was significantly lower with treatment B compared with treatment A. Treatment C did not show superior efficacy compared with treatment B. Conclusions: Our results suggest that early intervention with levocetirizine soon after onset of symptoms may attenuate these symptoms as effectively as prophylactic treatment before pollen dispersal. These results are important from the perspective of patient convenience and reduction of medical costs.

Recent decades have witnessed a rapid worldwide increase in chronic inflammatory disorders such as asthma. CD4(+) T helper 2 cells play critical roles in the pathogenesis of allergic airway inflammation, and CD69 expression on activated CD4 T cells is required to induce allergic inflammation in tissues. However, how CD69 mechanistically controls allergic inflammation remains poorly defined. In lymphoid tissues, CD69 regulates cellular retention through inhibition of S1P1 expression and requires no specific ligands to function. In contrast, we show herein that myosin light chain (Myl) 9 and Myl12 are new functional ligands for CD69. Blockade of CD69-My19/12 interaction ameliorates allergic airway inflammation in ovalbumin-induced and house dust mite-induced mouse models of asthma. Within the inflamed mouse airways, we found that the expression of My19/12 was increased and that platelet-derived My19/12 localized to the luminal surface of blood vessels and formed intravascular netlike structures. Analysis of nasal polyps of eosinophilic chronic rhinosinusitis patients revealed that My19/12 expression was increased in inflammatory lesions and was distributed within net-like structures in the intravascular space. In addition, we detected My19/12 in perivascular spaces where many CD69(+) cells were positioned within My19/12 structures. Thus, CD69-My19/12 interaction is a key event in the recruitment of activated CD69(+) T cells to inflamed tissues and could be a therapeutic target for intractable airway inflammatory diseases. Refereed/Peer-reviewed

Immunological memory has a central role in the adaptive immune systems that can efficiently eliminate pathogens such as virus and bacteria. Particularly, memory CD4 T cells function as a control tower of the adaptive immune systems. However, memory helper T (Th) cells are also involved in the pathogenesis of various chronic inflammatory diseases, including asthma. Recently, we have found IL-5-producing pathogenic population in memory Th2 cells in allergic asthma. We term this population memory-type ‘pathogenic Th2 cells (Tpath2 cells)’ in the airway. Several groups also reported distinct memory type Th2 populations, which produce a large amount of IL-5 or multiple cytokines in addition to IL-4 and IL-13. These populations seem to be responsible for the pathology of chronic inflammatory disorders. Our recent study has revealed that ST2 (a component of IL-33 receptor) expression on Tpath2 cells plays an important role for inducing pathogenicity in memory Th2 cells. Here, we highlight the regulation and function of IL-33 and ST2 on memory Th2 cells, and review their roles in the induction and progression of chronic airway inflammation in both mice and human systems.

Significance A substantial proportion of people have intractable chronic allergic diseases for which no curative treatment exists. A clear understanding of how these allergic diseases develop and persist is lacking. Here, unique ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue were found to be formed during chronic airway inflammation, and were critical in persistent inflammation. In addition, we identified a Thy1 + IL-7 + IL-33 + subset of lymphatic endothelial cells (LECs) that support the maintenance of memory-type pathogenic T helper 2 (Tpath2) cells. A similar population of IL-7 + IL-33 + LECs was found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, we revealed that Thy1 + IL-7–producing LECs control chronic allergic airway inflammation by supporting memory-type Tpath2 cells in human and mouse systems.

To evaluate the safety, immune responses, and antitumor responses after the administration of α-galactosylceramide (αGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 × 109/m2) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-γ-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-γ-producing cells (≥2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-γ-producing cells that result from αGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.

Background Many subjects are sensitized to Japanese cedar pollen but do not develop allergic rhinitis (AR). The aim of this study was to examine the immunologic parameters related to the development of AR in sensitized subjects. Methods The subjects were 33 adults who were sensitized to Japanese cedar pollen, but had not developed as of 2007. Cedar pollen–specific IgE (sIgE) and total IgE (tIgE) in serum, cedar pollen antigen (Cry j 1) Cry j–specific memory Th2 cell clone size, and the Cry j–specific induced regulatory T cell (iTreg) level were examined before and after the season in 2008. Results Eight of the 33 subjects developed cedar pollinosis. The sIgE titers before the season in these eight subjects did not differ from those in the subjects who did not develop pollinosis, but the titers after the season were significantly higher in the group that developed pollinosis. The sIgE/tIgE ratio increased in almost all subjects, but the ratio was significantly higher before the season in the subjects who developed pollinosis. Cry j–specific Th2 cells were detected in all subjects, but the clone size only increased in those that developed pollinosis. The Cry j–specific iTreg population did not differ between the two groups. Conclusion A high sIgE/tIgE ratio before the season may be predictive of development of pollinosis, and an increase in the allergen-specific Th2 clone size during the pollen season could be a biomarker for pollinosis. The role of allergen-specific iTreg cells in the development of pollinosis could not be clarified in this preliminary study.

Human Valpha24 natural killer T (NKT) cells are activated by the specific ligand, alpha-galactosylceramide (alpha-GalCer), in a CD1d-dependent manner. Potent anti-tumor activity of activated NKT cells has been previously demonstrated.We conducted a phase I study with alpha-GalCer-pulsed antigen presenting cells (APCs) administered in the nasal submucosa of patients with head and neck cancer, and evaluated the safety and feasibility of such a treatment. Nine patients with unresectable or recurrent head and neck cancer received two treatments 1 week apart, of 1 x 10(8) of alpha-GalCer-pulsed autologous APCs into the nasal submucosa.During the clinical study period, no serious adverse events (Common Terminology Criteria for Adverse Events version 3.0 greater than grade 3) were observed. After the first and the second administration of alpha-GalCer-pulsed APCs, an increased number of NKT cells was observed in four patients and enhanced natural killer activity was detected in the peripheral blood of eight patients.The administration of alpha-GalCer-pulsed APCs into the nasal submucosa was found to be safe and induce anti-tumor activity in some patients.

Memory CD4 + T helper (Th) cells provide long-term protection against pathogens and are essential for the development of vaccines; however, some antigen-specific memory Th cells also drive immune-related pathology, including asthma. The mechanisms regulating the pathogenicity of memory Th cells remain poorly understood. We found that interleukin-33 (IL-33)-ST2 signals selectively licensed memory Th2 cells to induce allergic airway inflammation via production of IL-5 and that the p38 MAP kinase pathway was a central downstream target of IL-33-ST2 in memory Th2 cells. In addition, we found that IL-33 induced upregulation of IL-5 by memory CD4 + Tcells isolated from nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, IL-33-ST2-p38 signaling appears to directly instruct pathogenic memory Th2 cells to produce IL-5 and induce eosinophilic inflammation. Refereed/Peer-reviewed

Recent observations have suggested significant worldwide increase in the prevalence of allergic rhinitis and cedar pollinosis. In Japan, Japanese cedar (Cryptometria japonica) and Japanese cypress (Chamaecyparis obtusa) pollens are considered to be the major unique allergens and their extent of dispersal is quite large, travelling more than 100 km and thus causing serious pollinosis. Cedar pollinosis is a typical type 1 allergic disease by an adaptive immune response that occurs through the induction of allergen-specific effector T cells from naive T cells. We examined the number of Japanese cedar pollen specific memory Th cells in the peripheral blood of the patients and found that the cedar pollen specific IL-4-producing Th2 memory cells increased during the pollen season and decreased during the off-season. However, more than 60% of the cedar-specific memory Th2 cells survived up to 8 months after the pollen season. Natural killer T(NKT) cells represent a unique lymphocyte subpopulation and their activity is not restricted to MHC antigens. NKT cells play an important role in innate immunity, however, the participation in development of allergic rhinitis could not be clarified.