Effect of tiotropium bromide on airway inflammation and remodelling in a mouse model of asthma.

BACKGROUND: Tiotropium bromide, a long acting muscarinic receptor inhibitor, is a potent agent for patients with bronchial asthma as well as chronic obstructive pulmonary disease. OBJECTIVE: The aim of this study was to evaluate whether tiotropium bromide can inhibit allergen-induced acute and chronic airway inflammation, T helper (Th)2 cytokine production, and airway remodelling in a murine model of asthma. METHODS: Balb/c mice were sensitized and challenged acutely or chronically to ovalbumin (OVA). The impact of tiotropium bromide was assessed using these mice models by histologic, morphometric, and molecular techniques. Moreover, the effect of tiotropium bromide on Th2 cytokine production from purified human peripheral blood mononuclear cells (PBMCs) was assessed. RESULTS: Treatment with tiotropium bromide significantly reduced airway inflammation and the Th2 cytokine production in bronchoalveolar lavage fluid (BALF) in both acute and chronic models of asthma. The levels of TGF-beta1 were also reduced by tiotropium bromide in BALF in a chronic model. The goblet cell metaplasia, thickness of airway smooth muscle, and airway fibrosis were all significantly decreased in tiotropium bromide-treated mice. Moreover, airway hyperresponsiveness (AHR) to serotonin was significantly abrogated by tiotropium bromide in a chronic model. Th2 cytokine production from spleen cells isolated from OVA-sensitized mice was also significantly inhibited by tiotropium bromide and 4-diphenylacetoxy-N-methylpiperidine methiodide, which is a selective antagonist to the M3 receptor. Finally, treatment with tiotropium bromide inhibited the Th2 cytokine production from PBMCs. CONCLUSION: These results indicate that tiotropium bromide can inhibit Th2 cytokine production and airway inflammation, and thus may reduce airway remodelling and AHR in a murine model of asthma.

Inhibitory effects of suplatast tosilate on the differentiation and function of monocyte-derived dendritic cells from patients with asthma.

BACKGROUND: Dendritic cells (DCs) are antigen-presenting cells that efficiently activate T cells. OBJECTIVE: We examined the effects of suplatast tosilate, which prevents T-helper type 2 responses, on the differentiation and function of monocyte-derived DCs (moDCs). METHODS: DCs were differentiated in vitro from peripheral monocytes from patients with asthma by the addition of granulocyte macrophage colony-stimulating factor and IL-4 in the presence or absence of suplatast tosilate. Cell surface molecules (CD1a, CD14, CD80, CD83, CD86, HLA-DR) on immature and mature DCs were analysed with flow cytometry, and the secretion of CC chemokine ligand (CCL)17 (thymus and activation-regulated chemokine), IL-12p70, IL-12p40, and IL-10 was measured with an ELISA. We also studied the proliferative responses of allogeneic CD4(+) T cells from healthy subjects to DCs differentiated in the presence of suplatast tosilate. In addition, the production of IFN-gamma and IL-5 by CD4(+) T cells after coculture with untreated DCs or suplatast tosilate-treated DCs was measured with ELISA. RESULTS: Suplatast tosilate significantly inhibited the expression of CD1a, CD80, and CD86 on immature DCs and of CD1a, CD80, CD83, and CD86 on mature DCs. Suplatast tosilate also significantly inhibited the secretion of CCL17, IL-12p70, and IL-12p40; however, the secretion of IL-10 was not affected. The proliferative responses of allogeneic CD4(+) T cells to suplatast tosilate-treated DCs were suppressed. Moreover, suplatast tosilate-treated DCs had an impaired capacity to stimulate CD4(+) T cells to produce IFN-gamma and IL-5. CONCLUSION: Suplatast tosilate inhibits the differentiation, maturation, and function of moDCs.

Association between lipid peroxidation and inflammation in obstructive sleep apnoea.

In the present study, the authors examined the relationship between lipid peroxidation and inflammation in patients with obstructive sleep apnoea (OSA). A total of 40 obese patients with OSA were studied, along with 18 obese and 12 lean subjects without OSA. Overnight excretion of 8-isoprostane in urine and serum levels of high-sensitivity C-reactive protein (hsCRP) were measured. In addition, the effects of 3 months' treatment with nasal continuous positive airway pressure (nCPAP) were studied in 20 obese patients with moderate-to-severe OSA. Overnight urinary excretion of 8-isoprostane and serum levels of hsCRP were significantly higher in patients with moderate-to-severe OSA compared with patients with mild OSA and obese or lean subjects without OSA. Overnight urinary excretion of 8-isoprostane significantly correlated with apnoea-hypopnoea index, duration of hypoxia during sleep, body mass index, and serum levels of hsCRP in patients with OSA. The severity of OSA was an independent factor predicting the urinary excretion of 8-isoprostane. nCPAP significantly decreased urinary excretion of 8-isoprostane and serum levels of hsCRP. In conclusion, these results suggest that both obstructive sleep apnoea severity and obesity can independently contribute to elevations in urinary excretion of 8-isoprostane. Therefore, obstructive sleep apnoea may increase the risks of cardiovascular morbidity in obese patients.

Inhibitory effects of fluvastatin on cytokine and chemokine production by peripheral blood mononuclear cells in patients with allergic asthma.

BACKGROUND: Statins have anti-inflammatory effects on immune cells. OBJECTIVE: To investigate the immunomodulatory effects of fluvastatin on peripheral blood mononuclear cells (PBMCs) after allergen-specific and non-allergen-specific stimulation in patients with asthma and in healthy subjects. METHODS: PBMCs from seven patients with asthma who showed elevated immunoglobulin (Ig)E to house dust mite were isolated and stimulated with Dermatofagoides farinae, purified protein derivative, and phytohaemagglutinin (PHA) in the presence or absence of fluvastatin. PBMCs from seven healthy subjects were stimulated with PHA. The effects of fluvastatin on cell proliferation and production of cytokines (interferon [IFN]-gamma and interleukin [IL]-5) and chemokines (chemokine CXC motif, ligand [CXCL10], and CC chemokine ligand [CCL17]) were measured. Migration of T helper (Th)1 and Th2 cell lines was also investigated. The expression of CXCR3 and CCR4 was analysed with flow cytometry. Steroid-insensitive PBMCs induced by preculture with IL-2 and IL-4 were also evaluated. Some experiments were performed in the presence of mevalonic acid. RESULTS: Fluvastatin inhibited the proliferation of PBMCs and decreased the production of IL-5, IFN-gamma, CCL17, and CXCL10 after allergen-specific and non-allergen-specific stimulation; all these effects, except for decreased CXCL10 production, were partially reversed by mevalonic acid. Culture supernatants obtained in the presence of fluvastatin prevented the migration of Th1 and Th2 cell lines in a dose-dependent manner. In addition, CCR4 and CXCR3 expression on CD4(+) T cells was not affected by the presence of fluvastatin. Fluvastatin inhibited the proliferative response of steroid-insensitive PBMCs to phytohaemagglutinin. CONCLUSION: Fluvastatin has inhibitory effects on cytokine and chemokine production, and thus might be used as a potential therapeutic agent in severe asthma.

Cough receptor sensitivity to capsaicin does not change after allergen bronchoprovocation in allergic asthma.

BACKGROUND: The relationship between cough receptor sensitivity and eosinophilic inflammation of the airway in patients with asthma remains unclear. METHODS: Eighteen patients with asthma sensitised to house dust mite (HDM) were enrolled in a randomised parallel group study. Patients with asthma whose main symptom was cough were not enrolled in the study. Half the patients were randomly assigned to inhale saline and the other half to inhale HDM allergen. Cough receptor sensitivity to capsaicin, airway responsiveness to histamine, and sputum eosinophils analysed with hypertonic saline inhalation were investigated before and 24 hours after saline or HDM allergen bronchoprovocation. RESULTS: Patients inhaling saline showed no significant changes in sputum eosinophils (from 7.87% (95% confidence interval (CI) 5.08 to 12.19) to 8.60% (95% CI 3.03 to 14.18); p=0.97), airway responsiveness to histamine (from 726.68 micro g/ml (95% CI 251.90 to 2096.36) to 773.01 micro g/ml (95% CI 251.36 to 2377.23); p=0.96), or capsaicin sensitivity (from 7.23 micro M (95% CI 2.45 to 21.31) to 7.24 micro M (95% CI 2.46 to 21.31); p=0.96). Early asthmatic response was induced in all patients, and late asthmatic response was observed in six of nine patients inhaling HDM allergen. Although there were significant increases in sputum eosinophils (from 9.83% (95% CI 6.78 to 14.27) to 21.00% (95% CI 13.85 to 28.15); p<0.01) and airway responsiveness to histamine (from 784.16 micro g/ml (95% CI 318.24 to 1932.24) to 377.81 micro g/ml (95% CI 118.43 to 1205.24); p<0.05) 24 hours after HDM allergen inhalation compared with baseline levels, capsaicin sensitivity did not change significantly (from 5.75 micro M (95% CI 1.91 to 17.30) to 6.20 micro M (95% CI 2.21 to 17.38); p=0.77). CONCLUSIONS: These findings suggest that cough receptor sensitivity to capsaicin is not associated with eosinophilic inflammation of the airway in patients with allergic asthma whose main symptoms are wheezing and dyspnoea but not cough.

Suplatast tosilate inhibits thymus- and activation-regulated chemokine production by antigen-specific human Th2 cells.

BACKGROUND: Suplatast tosilate is an anti-allergic agent that suppresses cytokine production by human Th2 cells. OBJECTIVE: We investigated the effects of suplatast tosilate on the production of thymus- and activation-regulated chemokine (TARC) by T cells from allergic patients with asthma. METHODS: Purified protein derivative (PPD)-specific Th1 cell lines and Dermatophagoides farinae (Der f)-specific Th2 cell lines were established from nine patients with house dust mite-allergic asthma. The effects of suplatast tosilate on mRNA expression of TARC and protein production of TARC from antigen-specific Th1 or Th2 cell lines were investigated after stimulation with relevant antigens or phytohemagglutinin (PHA). In addition, the effects of IL-4, IL-10, and IFN-gamma on TARC production by Der f-specific Th2 cell lines in the presence or absence of suplatast tosilate were studied. RESULTS: Although PPD-specific Th1 cell lines did not produce TARC after stimulation with PPD antigen or PHA, stimulation of Der f-specific Th2 cell lines with Der f antigen or PHA increased production of TARC. Suplatast tosilate significantly and dose-dependently inhibited production of TARC by Der f-specific Th2 cell lines stimulated with either Der f antigen (76.5% inhibition at 100 microg/mL, P < 0.01) or PHA (81.9% inhibition at 100 microg/mL, P < 0.01). TARC production by Der f-specific Th2 cell lines was significantly increased only by activation with IL-4 but not with IL-10 or IFN-gamma; this increase in TARC production was significantly inhibited by suplatast tosilate (97.5% inhibition at 100 microg/mL, P < 0.01). CONCLUSION: Suplatast tosilate inhibits TARC production by human Th2 cells. Therefore, this agent inhibits both Th2 cytokine and Th2 chemokine and may be a useful anti-allergic agent.

[Leukotriene modifiers].

Cysteinyl leukotriene (CysLT) C4, D4, and E4 play key roles in asthma. CysLTs are newly generated after cellular activation and are produced by eosinophils, mast cells, alveolar macrophages, and neutrophils. Pharmacological actions of CysLTs include potent bronchoconstriction, increased microvascular leakage and mucus secretion, chemoattraction of eosinophils, acceleration of eosinophil apoptosis, and proliferation of human airway smooth muscle. Recent studies demonstrated that CysLT1 receptors are distributed on CD34+ stem cells, eosinophils, monocytes, macrophages, basophils, and B cells in addition to airway smooth muscle. Because of these wide variety of distribution, Cys LTs may have another important roles in airway inflammation. CysLT1 receptor antagonist is widely used and found to be beneficial for the chronic management of asthma especially to symptomatic patients who had already been treated with moderate to high doses of inhaled corticosteroids and also to mild to moderate steroid-naive asthmatic patients.

[Thromboxane A2 synthase inhibitor and receptor antagonist].

Thromboxane A2 (TxA2) plays an important role in asthma. TxA2 are newly generated after cellular activation and are produced by not only platelets but also eosinophils, basophils, alveolar macrophages, and neutrophils. Pharmacological actions of TxA2 include potent bronchoconstriction, increased microvascular leakage, impairment of mucociliary clearance, and induction of airway hyperresponsiveness. Recent study demonstrated that TxA2 receptor antagonist decreased the number of eosinophils in bronchial biopsy specimens, suggesting that this type of agent possesses anti-inflammatory actions in asthma. Furthermore, addition of TxA2 synthase inhibitor significantly increased the PEF values in the persistent asthmatic patients despite the treatment with moderate-dose of inhaled corticosteroids. Therefore, these results suggest that TxA2 synthase inhibitor and receptor antagonist are useful for the treatment with symptomatic patients who had already been treated with inhaled corticosteroids.

Step-down and step-up therapy in moderate persistent asthma.

BACKGROUND: A step-down therapy may be more beneficial for the management of asthma than a step-up therapy. METHODS: Eighty-two asthmatic patients with moderate persistent asthma were enrolled in the study and randomized into three groups. One group of patients received 400 microg/day of beclomethasone dipropionate (BDP) for 4 weeks and then 800 microg/day for another 4 weeks (step-up group). The other two groups of patients received 1,200 microg/day of BDP for 4 weeks with or without short-term oral steroid (prednisolone, 0.5 mg/day for 1 week) and then 800 microg/day for another 4 weeks (step-down group). Severe exacerbation of asthma, asthma symptoms, respiratory function and rescue use of inhaled beta(2)-agonists were monitored. If asthma was well controlled, the dose of BDP was decreased every 3 months and if asthma was exacerbated, the dose of BDP was increased until 8 months after the initial treatment. RESULTS: Twenty-two patients during the run-in period, 4 patients in the step-up group, 2 patients in the step-down group treated with a high dose of BDP and no patients in the step-down group with oral steroids during first 4 weeks dropped out because of severe exacerbation of asthma. Although asthma symptoms and respiratory function significantly improved 8 weeks after the therapy in all groups, more significant and prompt improvements of these parameters were observed in patients of the step-down group than in patients of the step-up group after the first 2 weeks of treatment. Furthermore, step-down therapy with short-term oral steroid resulted in the lowest maintenance doses of BDP at 8 months of the three groups. CONCLUSIONS: These results suggest that step-down therapy starting with a high dose of inhaled steroid and short-term oral steroid is more effective in gaining prompt control of asthma and reducing the severe exacerbation of asthma and the maintenance dose of inhaled steroids than a step-up therapy starting with a low dose of inhaled steroids in patients with moderate persistent asthma.

Analysis of IL-12 receptor beta 2 chain expression of circulating T lymphocytes in patients with atopic asthma.

Th2 cell predominance relative to Th1 cells contributes to pathological immune responses in patients with atopic asthma. IL-12 is a key cytokine in the induction of Th1 cells, and downregulation of IL-12 production is reported in these patients. However, IL-12 receptor expression of their T lymphocytes has not been clarified. In this study, expression of IL-12 receptor beta 2 on T cells and secretion of cytokines which affect IL-12 receptor beta 2 expression by their PBMC were examined. We found that IL-12 receptor beta 2 expression of the T cells is reduced. This is partly due to the diminished production of IL-12 and enhanced secretion of IL-4 by their PBMC. IL-18 production is not significantly modulated in these patients. Furthermore, intrinsic defects of the CD4(+) T cells, which reduce their IL-12 receptor beta 2 expression in response to IL-12 and/or IL-18 stimulation, are evident and are importantly involved in the Th1/Th2 imbalance of patients with atopic asthma.

Interleukin-10 relieves the inhibitory effects of interferon-gamma on normal human lung fibroblasts.

Interleukin-10 (IL-10) is an important cytokine that suppresses the production of cytokines and chemokines by immune cells. IL-10 has been suggested to be involved in chronic inflammatory responses including the remodeling process in the lung. We investigated the effects of IL-10 on proliferation, extracellular matrix and cytokine production in normal human lung fibroblasts (NHLF). Human IL-10 (hIL-10) complementary DNA (cDNA) was transfected into NHLF using an adenoviral vector. No significant changes were observed in proliferation, fibronectin or procollagen type I production in the NHLF transfected with hIL-10 cDNA. Interferon (IFN)-gamma significantly inhibited cell proliferation and extracellular matrix production in a dose-dependent manner. Transfection of hIL-10 cDNA significantly relieved the suppressive effects of IFN-gamma in NHLF. Transforming growth factor (TGF)-beta production was not significantly affected by either transfection of hIL-10 cDNA or the addition of IFN-gamma. The relief of the suppressive function of IFN-gamma by IL-10 suggested that IL-10 is indirectly involved in the remodeling process in the lung interstitium.

Correlation between respiratory function and airway inflammation in asthma.

BACKGROUND: Eosinophilic airway inflammation is thought to be associated with airflow limitation and airway hyperresponsiveness. METHODS: Spirometry, peak expiratory flow (PEF) measurement, histamine challenge test, and sputum induction with hypertonic saline inhalation were performed in 70 asymptomatic patients with asthma who were treated with bronchodilators or an inhaled corticosteroid (beclomethasone dipropionate, 400-800 microg/day) or both for more than 2 months. The relationships between the sputum eosinophils, respiratory function, and airway responsiveness to histamine were investigated. RESULTS: Induced sputum was obtained from 53 patients. Although significant correlations between sputum eosinophils and forced expiratory volume in 1 s/forced vital capacity x 100% (FEV1%) or maximum expiratory flow at 25% of the forced vital capacity (V25) divided by height (V25/Ht) were observed, no significant correlations were found between sputum eosinophils and percent predicted PEF (%PEF) or airway responsiveness to histamine. Furthermore, airway responsiveness to histamine was not correlated with FEV1%, V25/Ht or %PEF. CONCLUSION: Single-point measurements of FEV1% and V25/Ht but not PEF or airway responsiveness to histamine correlate with the degree of airway inflammation evaluated indirectly with induced sputum.

Effect of suplatast tosilate (IPD-1151T) on cytokine production by allergen-specific human Th1 and Th2 cell lines.

Suplatast tosilate (IPD-1151T) is an antiallergic agent that suppresses airway eosinophil infiltration in asthma. We investigated the effects of IPD-1151T on proliferative response and cytokine production by human antigen-specific T cell lines. Purified protein derivatives (PPD)-specific T helper 1 (Th1) cell lines and Dermatophagoides farinae (Der f)-specific T helper 2 (Th2) cell lines were established from patients with asthma sensitized with house dust mite. Stimulation of PPD-specific and Der f-specific T cell lines with relevant antigens resulted in production of mostly interferon (IFN)-gamma and of interleukin (IL)-4 and IL-5, respectively. IPD-1151T did not inhibit the proliferative responses of either the Th1 or Th2 cell line to antigens. Although IPD-1151T did not inhibit IFN-gamma production by PPD-specific Th1 cell lines, it did inhibit IL-4 and IL-5 production by antigen-stimulated Der f-specific Th2 cell lines in a dose-dependent manner. IPD-1151T directly inhibited cytokine production by Der f-specific Th2 cell lines stimulated with immobilized anti-CD3 antibodies. Although IPD-1151T did not inhibit the clonal expansion of memory T cells among PBMCs into PPD-specific Th1 and Th2 cell lines, it did inhibit IL-4 and IL-5 production by Der f-specific Th2 cell lines but not IFN-gamma production by PPD-specific Th1 cell lines. These results suggest that IPD-1151T selectively inhibits Th2-type cytokine production.

IL-10 induces a Th2 cell tolerance in allergic asthma.

BACKGROUND: Interleukin (IL)-10 induces a long-term antigen-specific anergy in human CD4+ T cells. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from house dust mite (Dermatophagoides farinae, Der f)-sensitized asthmatic patients. PBMCs were stimulated with Der f antigen for 72 h immediately after purification or after 48 h of resting culture with medium, and IL-10 and IL-5 in the culture supernatant were measured. PBMCs were also stimulated with Der f antigen for 7 days either immediately after purification or after 48 h of resting culture, after which cells were collected. Secondary proliferative responses of these cells to stimulation for 3 days with Der f antigen and mitomycin C-treated PBMCs as antigen-presenting cells or with phorbol myristate acetate (PMA) plus calcium ionophore were investigated. RESULTS: Stimulation of PBMCs with Der f antigen immediately after purification significantly increased the proliferative response and IL-5 production. Stimulation of PBMCs with Der f antigen after resting culture with medium alone for 48 h significantly decreased IL-5 production and markedly increased IL-10 production. Although activation of cells with Der f antigen immediately after purification significantly increased secondary proliferative responses, stimulation after 48 h of resting culture failed to increase secondary proliferative responses. However, proliferation recovered when cells were activated with PMA plus calcium ionophore. CONCLUSION: These results suggest that antigen-specific Th2 cells are anergized by IL-10 and that Th2 cell tolerance may suppress eosinophilic inflammation in allergic asthma.

Protein tyrosine phosphorylation: A possible common signaling pathway in human Th1 and Th2 cell clones.

BACKGROUND: It has been reported that protein tyrosine phosphorylation is essential for cytokine production in mouse Th1 cells but not in Th2 cells. However, little is known about the difference of signal transduction between human antigen-specific Th1 and Th2 cell clones. METHODS: Purified protein derivative-specific Th1 and Dermatophagoides farinae-specific Th2 cell clones were established. T cell clones were stimulated with anti-CD3 Abs and further treated with goat antimouse immunoglobulin Abs for cross-linking of TCR/CD3 complex. RESULTS: In contrast to murine Th2 clones, tyrosine phosphorylation including both ZAP-70 and phospholipase-C-Al was necessary for cell activation in both types of human T cell clones. This was further supported by the observation that genistein (protein tyrosine kinase inhibitor) inhibits IFN-A production for Th1 and IL-4 for Th2 in a dose-dependent manner. CONCLUSION: Protein tyrosine phosphorylation is thus an essential component in transducing the activation signal from TCR-CD3 complex both in human Th1 and Th2 cells.

Effect of rush immunotherapy on airway inflammation and airway hyperresponsiveness after bronchoprovocation with allergen in asthma.

BACKGROUND: Rush immunotherapy (RIT) has been shown to be effective in allergic asthma. OBJECTIVE: We investigated the mechanisms of RIT on the basis of cytokine production by T-cell lines and airway inflammation and responsiveness. METHODS: Subjects were 8 patients with house dust mite-allergic asthma treated with dust mite extract RIT for 6 months and 6 RIT-untreated control patients. IL-5 production by Dermatophagoides farinae -specific T-cell lines, eosinophil percentages, and eosinophil cationic protein (ECP) in induced sputum and airway responsiveness to allergen and histamine were evaluated before and after treatment. Changes in eosinophil percentages and ECP in induced sputum and responsiveness to histamine 24 hours after allergen inhalation were also studied. RESULTS: After 6 months of RIT, percentages of total eosinophils (43. 0% +/- 6.90% to 16.8% +/- 2.48%; P <.01), percentages of EG2(+ ) eosinophils (32.6% +/- 6.39% to 19.7% +/- 4.68%; P <.01) and ECP (362.7 +/- 125.3 ng/mL to 26.2 +/- 5.15 ng/mL; P <.05) decreased in induced sputum, and IL-5 production by T-cell lines decreased (617 +/- 93.2 pg/mL to 200.0 +/- 34.1 pg/mL; P <.01). RIT decreased both early- and late-phase bronchoconstriction (early phase: 33.2% +/- 3. 46% to 25.4% +/- 1.42%; P <.03; late phase: 16.2% +/- 3.52% to 6.2% +/- 1.96%; P <.03) and suppressed increases in the percentages of total (61.8% +/- 4.89% to 42.0% +/- 4.67%; P <.01) and EG2-positive eosinophils (55.54% +/- 7.21% to 36.5% +/- 6.43%; P <.01) and ECP (685.6 +/- 217.0 ng/mL to 85.4 +/- 23.4 ng/mL; P <.05) in induced sputum after allergen inhalation. RIT also decreased airway responsiveness to dust mite (1:303.7 +/- 123.7 wt/vol to 1:65.0 +/- 13.2 wt/vol; P <.03) and to histamine before (397.1 +/- 206.9 microgra/mL to 1391.3 +/- 283.3 microgram/mL; P <.03) and after allergen inhalation (139.2 +/- 36.5 microgram/mL to 629.1 +/- 196.3 microgram/mL; P <.03). CONCLUSION: RIT decreases airway inflammation and airway hyperresponsiveness before and after bronchial provocation with allergen, possibly by inhibiting both allergen-specific T-cell- and mast cell-dependent pathways. RIT is an effective antiinflammatory treatment in allergic asthma.

Long-term analysis of allergen-specific T cell clones from patients with asthma treated with allergen rush immunotherapy.

Rush immunotherapy (RI), a modified allergen-specific immunotherapeutic procedure, is an effective treatment for extrinsic (atopic) asthma, although the precise mechanism of its action is unclear. We have thus investigated the effect of RI on T cell response in seven mite-allergen-sensitive asthmatic patients who were successfully treated with RI. The proliferative response to mite allergen profoundly decreased after 3 months of therapy compared to the response before therapy; the response, however, recovered 18 months after RI. Regarding cytokine production patterns of mite-specific T cells, RI brought about a shift in cytokine profiles from Th2 to Th0 or Th1 in mite-specific T cell clones. The data indicate that the efficacy of RI is due to modification of T cell responses to mite antigens. Allergen RI results in the conversion of Th2 to Th1 and Th0 cells and/or selection of Th1 and Th0 cells over Th2 cells and thus may improve both clinical symptoms and airway inflammation in asthmatics.

[Effect of slow-release theophylline on airway inflammation in bronchial asthma].

Theophylline has been used as a bronchodilator in acute and chronic asthma management but recent evidences suggest that it has anti-inflammatory effects. Therefore, we investigated the therapeutic effect of slow-release theophylline in mild to moderate asthmatic patients. Symptomatic 19 patients with mild asthma who were treated with inhaled beta 2-agonist alone, and 17 subjects with moderate asthma who were treated with moderate dose of inhaled corticosteroid (beclomethasone dipropionate, BDP, 400-800 micrograms/day) were enrolled to the present study. After two-week run-in period, slow-release theophylline was administered for six to eight weeks and asthma symptoms, respiratory function, airway inflammation evaluated by the inhalation of hypertonic saline, and airway reactivity to histamine were investigated during observation period and after treatment. Asthma symptom score was significantly improved after theophylline treatment in both groups. Morning peak expiratory flow was significantly elevated but FEV1 was not significantly improved by the additional treatment with slow-release theophylline in both groups. Significant decreases in the percentages of total and EG2 + eosinophils in induced sputum demonstrated that slow-release theophylline has anti-inflammatory effect in patients with asthma despite the treatment with inhaled corticosteroid. Because recent reports suggest that theophylline may act as an anti-inflammatory drug even in low dose concentration, we also investigated the effect of plasma theophylline concentration on the airway inflammation. Patients were divided into two groups by the plasma concentration of theophylline, more than 10 micrograms/mL which is necessary to dilate airway and below 10 micrograms/mL, referred to as low dose concentration of theophylline. The results suggest that the administration of slow-release theophylline significantly decreased the percentages of both total and EG2 + eosinophils in induced sputum in both concentration groups. However, airway reactivity to histamine did not significantly change by the treatment. Taken together, we conclude that low dose treatment of slow-release theophylline has an anti-inflammatory effect and treatment with slow-release theophylline alone or the additional use with inhaled corticosteroid is an effective therapy for the management of mild to moderate asthma.