Interleukin-33 and alveolar macrophages contribute to the mechanisms underlying the exacerbation of IgE-mediated airway inflammation and remodelling in mice.

Allergen-specific IgE has long been regarded as a major molecular component of allergic asthma. Additionally, there is increasing evidence of the important roles of interleukin-33 (IL-33) in the disease. Here, we show that IL-33 and alveolar macrophages play essential roles in the exacerbation of IgE-mediated airway inflammation and remodelling. BALB/c mice passively sensitized with ovalbumin (OVA)-specific IgE monoclonal antibody (mAb) were challenged with OVA seven times intratracheally. The seventh challenge exacerbated airway inflammation and remodelling compared with the fourth challenge; furthermore, markedly increased expression of IL-33 in the lungs was observed at the fourth and seventh challenges. When anti-IL-33 or anti-ST2 antibody was administered during the fourth to seventh challenge, airway inflammation and remodelling were significantly inhibited at the seventh challenge. Because increases of IL-33(+) and ST2(+) alveolar macrophages and ST2(+)  CD4(+) T cells in the lungs were observed at the fourth challenge, the roles of macrophages and CD4(+) cells were investigated. Depletion of macrophages by 2-chloroadenosine during the fourth to seventh challenge suppressed airway inflammation and remodelling, and IL-33 production in the lung at the seventh challenge; additionally, anti-CD4 mAb inhibited airway inflammation, but not airway remodelling and IL-33 production. Meanwhile, treatment with 2-chloroadenosine or anti-CD4 mAb decreased IL-33-induced airway inflammation in normal mice; airway remodelling was repressed only by 2-chloroadenosine. These results illustrate that macrophage-derived IL-33 contributes to the exacerbation of IgE-mediated airway inflammation by mechanisms associated with macrophages and CD4(+) cells, and airway remodelling through the activation of macrophages.

Activity and toxicity of 2-CDA in Langerhans cell histiocytosis: a single institutional experience.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal proliferation of immature and abnormal bone marrow derived langerhans cells. Treatment is usually multimodal. Potent anti-monocyte as well as immunomodulatory activity of 2-CDA and its proven efficacy in many lymphoproliferative disorders has made 2-CDA a rational choice in treatment of LCH. AIM: To evaluate the efficacy and toxicity profile of 2-CDA in children with relapsed or refractory LCH. SETTING AND DESIGN: This is a pilot study and we present the initial data of the first seven patients treated at our institution. MATERIALS AND METHODS: Seven patients of relapsed and refractory LCH were enrolled from July 2000 to June 2004. The cohort of seven patients included six males and one female with a median age at initiation of cladribine was 2.25 years (range, 1.67 to 7.0 years). Three patients had received one prior chemotherapy regimen while the rest were heavily pretreated. Cladribine was administered over two hours IV daily for five days and repeated every four weeks. RESULTS: After a median of six courses of cladribine (range, 2 to 9), two (33%) patients achieved PR and two (33%) patients have SD on imaging but are clinically better. None experienced grade 3 or 4 hematologic toxicity. At a median follow-up of 19 months (range, 8 to 52 months), five patients remain alive and one patient has died. CONCLUSION: Our study shows that single agent 2-CDA is active and well-tolerated in children with relapsed or refractory LCH.

[Immunological markers of disease activity in the course of 2-CDA treatment of multiple sclerosis]. / Immunologiczne markery aktywnosci choroby w przebiegu leczenia kladrybina stwardnienia rozsianego.

52 clinically definite multiple sclerosis (MS) patients were treated with subcutaneous injection of 5 mg 2-CDA in 5 consecutive days. The injection courses were repeated 6 times in one month interval. The MRI pattern and immunological markers were studied in serum and CSF before and after 6 months of treatment. The obtained results suggest that treatment with 2-CDA has not any significant effect on humoral immunological events in multiple sclerosis, what is in contrast to some normalization of cellular immunopathological processes.