Over the past 20 years, there has been an enormous increase in the understanding of the pivotal role of cytokines in the initiation and persistence of allergic inflammation in asthma, and in causing the airway structural changes and associated physiologic abnormalities that characterize this disease. This research originated from the important findings of Parish and Luckhurst,1who reported that T cells from airways, but not from peripheral blood, that were obtained from asthmatic subjects released mediators that promoted eosinophil chemokinesis and chemotaxis, but not neutrophil chemokinesis and chemotaxis. Subsequently, a seminal study by Mosmann and colleagues2identified subsets of T-helper (Th) cells (designated Th1 and Th2) in mice by identifying a different array of cytokines that the cells were producing and suggested that these subsets played different roles in the induction of allergic inflammation. The cytokines produced by Th2 cells (which subsequently came to be known as Th2 cytokines) were interleukin (IL)-3, IL-4, IL-5, and IL-13, the so-called Th1 cytokines were IL-10 and interferon (IFN)-γ, while other cytokines, such as IL-12 and granulocyte-macrophage colony-stimulating factor, were produced by both subsets (Fig 1
). More recently, it has become clear that these designations, which are possible to make using mouse T cells, are much more complicated in humans. This information, however, had important implications for the pathogenesis of allergic asthma, as the IL-4 levels that are necessary for IgE isotype switching,3 for the up-regulation of vascular cell adhesion molecule-1,4and for Th cell commitment are increased in the airways of allergic asthmatic subjects5and might also be involved in causing allergen-induced airway eosinophilia.6In addition, the biological activity of IL-5 is very specifically focused on the development, differentiation, recruitment, activation, and survival of eosinophils.7Allergen inhalation increases the production of IL-5 in the airways as measured in airway mucosal T cells8and induced sputum.9Allergen inhalation also increases the number of peripheral blood eosinophils and lymphocytes containing intracellular IL-510and increases the proportion of bone marrow CD34+ progenitor cells expressing the α subunit of the IL-5 receptor,11 suggesting that the responsiveness of the bone marrow to IL-5 is a determinant of the magnitude of the eosinophilic responses to inhaled allergens. In addition, IL-13, which stimulates the same receptor as IL-4, is necessary for allergen-induced airway hyperresponsiveness (AHR)12in mouse models of allergic airway responses. Subsequently, Th2 cells were identified in the airway mucosa of allergic asthmatic subjects.13 This information resulted in the hypothesis that the up-regulation of Th2 cells, with an associated down-regulation of Th1 cells, is responsible for the development of allergic asthma (Fig 1).