Eosinophils play a central role in the inflammatory response associated with bronchial asthma. We studied the involvement of eosinophils in the development of airway hyperresponsiveness (AHR) in a mouse model of allergic airway sensitization. Sensitization of BALB/c mice to OVA via the airways induced allergen-specific T-cell responses, IgE production, immediate cutaneous hypersensitivity (ICH), and increased airway reactivity. Airway sensitization was associated with eosinophil infiltration of the airways and increased production of interleukin-5 (IL-5) in cultures of peribronchial lymph node cells. Treatment of OVA-challenged animals with anti-IL-5 antibody during the sensitization protocol completely abolished the infiltration of eosinophils into the lung tissue and prevented the development of AHR without affecting levels of allergen-specific IgE, cutaneous hypersensitivity and allergen-specific T cell responses. These findings demonstrate that infiltration of lung tissue by eosinophils, triggered by increased IL-5 production, is a major factor in the development of AHR in this mouse model of airway sensitization.

In a proportion of atopic asthmatics, exposure to a relevant antigen is followed by chronic inflammation in the airways leading to altered airway responsiveness (AR). However, the mechanisms underlying the development of airway hyperresponsiveness still remain unclear. To elucidate the relationship between IgE-mediated reactions and airway hyperresponsiveness, a murine model of passive sensitization and airway challenge with ovalbumin (

SummaryTo study the role ofCD8 + T cells in allergic sensitization, we examined the effects of in vivo depletion ofCD8 + T cells prior to sensitization on IgE production, immediate type cutaneous hypersensitivity and development of altered airway responsiveness. BALB/c mice were thymectomized and treated with anti-CD8 antibody resulting in depletion of CD8 + T cells (< 1%) in spleen and lymphoid tissues. In these mice, sensitization to ovalbumin (OVA) via the airways still resulted in IgE anti-OVA responses and immediate cutaneous reactions to OVA, but the animals were unable to develop airway hyperresponsiveness, eosinophil infiltration of the lung parenchyma, or IL-5 production in the local lymph nodes of the airway. Transfer of CD8 + T cells from naive animals during sensitization (on day 8 of the 10-d protocol) fully restored the ability to develop airway hyperresponsiveness and this was accompanied by IL-5 production and eosinophil accumulation in the lung. These data indicate a critical role for CD8 + T cells in the production of IL-5 and the development of altered airway responsiveness after antigen sensitization through the airways.

Cytokines play an important role in modulating inflammatory responses and, as a result, airway tone. IL-10 is a regulatory cytokine that has been suggested for treatment of asthma because of its immunosuppressive and anti-inflammatory properties. In contrast to these suggestions, we demonstrate in a model of allergic sensitization that mice deficient in IL-10 (IL-10؊͞؊) develop a pulmonary inflammatory response but fail to exhibit airway hyperresponsiveness in both in vitro and in vivo assessments of lung function. Reconstitution of these deficient mice with the IL-10 gene fully restores development of airway hyperresponsiveness comparable to control mice. These results identify an important role of IL-10, downstream of the inflammatory cascade, in regulating the tone of the airways after allergic sensitization and challenge. O ne of the basic characteristics of asthma is airway hyperresponsiveness (AHR), which increases after exposure to allergen. The level of responsiveness is demonstrated by showing increased responses to bronchoconstrictors such as methacholine (MCh). This heightened responsiveness is thought to result from a complex inflammatory cascade involving several cell types, including T lymphocytes and eosinophils (1, 2). T lymphocytes exert many of their effects by secreting an array of cytokines. In allergic asthma, type 2 T helper (Th) cell (Th2) cytokines dominate over Th1 cytokines and several studies suggest a critical role for IL-4, IL-5, and IL-13 in the development of AHR (3). The mechanisms underlying cytokinemediated influences on the tone of the airways are still largely unknown.IL-10 originally was described in mice as a factor inhibiting cytokine production from murine Th1 clones (4). Subsequent studies showed that IL-10 also can down-regulate Th2 clones and their production of IL-4 and IL-5 (5). In addition, IL-10 expresses a wide variety of effects on other immune cells, including stimulation of B cell differentiation and Ig secretion (6). The true biological effects of IL-10 have been difficult to delineate because the activities of this molecule on immune responsiveness vary considerably (7). However, it is known that adult mice deficient in IL-10 (IL-10Ϫ͞Ϫ) develop a CD4 T cell-dependent and IFN-␥-mediated enterocolitis (8).The data concerning the role of IL-10 in allergic inf lammation and AHR are contradictory. A few reports found reduced IL-10 mRNA expression both in peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) lymphocytes of asthmatic patients (5) whereas others have demonstrated elevated levels in asthmatics (9 -11). Because of its immunosupressive properties in vitro and in animal models, IL-10 has been suggested as a potential therapy of allergic inf lammation and asthma (12).To define the role of IL-10 in controlling the development of allergic inflammation and AHR, we used an established mouse model of eosinophilic airway inflammation and allergen-driven alterations in airway function. Here, we describe that IL-10-deficient mice, sensitized and chal...