Mouse models of allergic disease; how do they relate to asthma in man?

Asthma in man has long been an ill-defined disease of uncertain aetiology, and is well-known to include a multitude of complex cellular and molecular interactions, involving numerous mediators, cytokines and chemokines. However, there appears to be an increasing acceptance that the non-specific airway hyperresponsiveness, which is the hallmark of asthma, occurs as a result of damage caused by the accumulation of large numbers of activated eosinophils within the airway wall [1,2]. Although the eosinophils are considered to be the major effector cells in the disease there is abundant evidence that the production, recruitment, activation and survival of these cells in airway tissues are orchestrated by cytokines produced by CD4'^ T lymphocytes of the TH2-like subtype [3]. A growing dilemma for those of us interested in the discovery and development of new drugs for the treatment of asthma is that the more we learn about the pathophysiology of this increasingly complex disease, the more difficult it has become to identify the critical molecular target, or targets, which may provide new opportunities for therapeutic intervention. One potential bright light on the horizon has been the introduction of murine models of antigen-induced bronchopulmonary eosinophilia in which the mechanisms of allergic airway disease can be explored [4—7]. The advantages of using mice for potential in vivo models of asthma are obvious; their extensive use in immunology research has provided us with a host of reagents with which to explore cellular and molecular mechanisms involved in the pathophysiology of airway disease, and the availabilty of transgenic and 'knock-out' mice for the multitude of adhesion molecules, cytokines and cells which have been implicated in asthma, will provide invaluable opportunities to study the mechanisms of allergic tissue inflammation. The identification in asthmatics of a subset of CD4 T cells exhibiting a profile of cytokine generation (interleukins-4, 5, 10 and 13) similar to that originally described for TH2 lymphocytes in mice [8] offers some reassurance that our animal models and clinical asthma may be moving onto common ground. Over the past 2-3 years there has been a marked increase in the number of publications appearing in the scientific literature which describe mouse models of allergic airway disease [4-7] in which mechanisms, thought to be relevant to asthma in man have been explored. The paper by Nagai et al., in this issue of Clinical and Experimental Allergy is one such example [9]. They describe a model of antigen challenge in sensitized mice, in which the presumably IL-5-dependent lung eosinophilia is divorced from antigen-induced changes in airway responsiveness. A similar claim has been made for a dissociation of airway responsiveness and bronchoalvoiar lavage cell composition in sensitized guinea-pigs [10]. Do we then make the tacit assumption that antigen-induced eosinophilia is an epi-phenomenon and that we should ignore the mountain of accumulated clinical evidence which demonstrates a link between the T cell-orchestrated influx of eosinophils into the airway wall and airway hyperreactivity in man, and in animal models including primates [11]?