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Background: IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma. Methods: Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation. Results: When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV1%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively ( P < 0.01). The degree of attenuation in the EAR [maxFEV1% (mean ± SE) 26.5 ± 2.8% vs placebo 31.0 ± 2.8%, P = 0.059] and LAR (15.6 ± 2.9% vs placebo 19.0 ± 2.9%, P = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed. Conclusions: The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated. [ABSTRACT FROM AUTHOR]

Background:  Dendritic cells are key contributors to initiation and maintenance of T-cell immunity to inhaled allergen. The purpose of this study was to enumerate the changes in peripheral blood myeloid (mDCs) and plasmacytoid dendritic cells (pDCs), the DCs expressing chemokine receptor 6 (CCR6) and chemokine receptor 7 (CCR7), following diluent and allergen inhalation in asthmatic subjects. Methods:  Peripheral blood was obtained from 16 allergic asthmatic subjects before and at 0.5, 1, 2, 3, 4, 6, 24, and 48 h after inhaled diluent and allergen challenges. Dendritic cells were enumerated using flow cytometry. Results:  Allergen inhalation significantly reduced mDCs at 6 h (21.3 ± 2.0 vs 15.0 ± 1.8/μl blood; P < 0.05) and 24 h (21.5 ± 3.4 vs 16.4 ± 2.4/μl blood; P < 0.05) after challenge. Circulating pDCs were significantly lower than baseline up to 24 h after both allergen and diluent challenges. There was a significant efflux of CCR6+ mDCs from peripheral blood at 6 h and CCR6+ pDCs at 4 h after allergen challenge, when compared with diluent. There was no difference in the number of circulating CCR7+ mDCs or pDCs after diluent or allergen challenges. Conclusions:  Peripheral blood mDCs and CCR6+ mDCs, but not pDCs, are reduced up to 24 h after allergen inhalation. Thus, allergen inhalation causes trafficking of immature CCR6+ DCs from blood into the airway, while that of the trafficking of the mature CCR7+ DCs from the airways into the regional lymph nodes probably occurs through the lymphatic system. [ABSTRACT FROM AUTHOR]

Background The predominance of T-helper type 2 (Th2) lymphocytes is thought to underlie the pathogenesis of asthma. Allergen inhalation challenge in atopic asthmatic subjects is associated with decreased interferon-γ (IFN-γ) positive CD4+ and CD8+ lymphocytes in peripheral blood and induced sputum. Objective This study examined the effects of an inhaled corticosteroid on these previously described allergen-induced changes in circulating Th1 and Th2 lymphocytes. Methods Subjects were randomized to 7 days of placebo, 40 or 80 μg ciclesonide in a crossover study. Airway responses and peripheral blood were measured before and after treatment, and 24 h after allergen challenge. Results Ciclesonide 40 and 80 μg significantly attenuated the late response and sputum eosinophils at 8 h post-allergen ( P<0.05). Circulating IFN-γ positive CD4+ lymphocytes decreased after allergen challenge with placebo ( P<0.05), and this was inhibited by 40 μg ciclesonide treatment ( P<0.05). There was no effect of allergen inhalation or ciclesonide on IL-4-positive CD4+ lymphocytes or IFN-γ and IL-4-positive CD8high lymphocytes. The allergen-induced change of IFN-γ/IL-4 ratio on CD4+ cells correlated with the allergen-induced change of peripheral blood eosinophils. Conclusions The results of this study suggest that attenuation of allergen-induced airway responses by ciclesonide may be mediated through regulation of IFN-γ-positive CD4+ cells. [ABSTRACT FROM AUTHOR]