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Mice Are a Good Model of Human Airway Disease

National Jewish Medical and Research Center Denver, Colorado

Exposure of sensitized mice to airway allergen challenge elicits a series of responses, including increases in interleukin (IL)-4, IL-5, and IL-13 levels, a decrease in IL-10, an initial but transient neutrophil infiltration of the airways followed by a sustained eosinophilic and lymphocytic inflammatory response, goblet cell metaplasia and mucus hyperproduction, and alterations in airway function (1, 2). Mice can develop both an early- and a late-phase response (3). In secondary and tertiary challenge models, these responses may develop more quickly and substantially. Under some chronic challenge protocols, there is evidence for subbasement membrane fibrosis and smooth muscle hyperplasia (4, 5). Responses are allergen-specific and have been induced after allergen challenge not only to ovalbumin, but also with ragweed, dust mite, and cat peptides. In many ways, allergen challenge of sensitized individuals parallels the changes seen in mice.

Does this not establish the mouse as a model of human allergic airway disease, even a good model? There are important differences between the two species; it is hard to mimic the repeated exposure to allergen that individuals with asthma endure over time. The airways of humans are unique, with more branches than in other species, especially mice, and they exhibit complex neurogenic control pathways. Murine eosinophils appear to be refractory to the stimuli that cause human eosinophils to discharge their contents (6, 7). Debate on the role eosinophils play in allergic airway disease continues in mice and humans (8–11), with both eosinophil-dependent and -independent pathways emerging as important, even differences related to the level of the airways targeted by these pathways (12). Perhaps eosinophil degranulation is not important in human asthma either, but these cells, even in the absence of degranulation, control processes in disease pathogenesis that are common to all species (7, 13).

What have murine models contributed to our understanding of asthma? The major contributions have been in furthering understanding of the immune/inflammatory responses that follow sensitization and challenge. Our concept of the role of T cells, their heterogeneity, and specialized functions all first emerged in the mouse and we rapidly moved to confirm these findings in humans. Virtually every therapeutic target has emerged from studies in murine models, including cytokine/chemokine targets or their receptors, signaling molecules, mediator inhibitors, and others. Even the most recent trials with immunostimulatory sequences, allergen DNA conjugates or CpG oligonucleotides, were derived from basic studies in murine models (14).

Why then, in the face of so many contributions to our basic understanding of allergic inflammation and airway hyperresponsiveness, has there developed a vocal minority of criticism and cries of lack of relevance of the murine models to human disease? The answers lie in several areas. Since the introduction of inhaled corticosteroids, there has been little new in the way of therapeutics that packs a punch. Thus, mediator antagonists, leukotriene modifiers, anti-immunoglobulin E, and targeting cytokines (IL-4, IL-5, IL-12, and IL-18) have not provided the benefit predicted from studies in murine models (15). This has been frustrating for clinical investigators. Why would therapies that were so obviously effective in murine models have limited benefit in humans? This is the crux of the issue and the fundamental source of the concerns and negativism about the relevance of murine models.

Asthma is a heterogeneous disease in man, and is clearly so in mice. Witness the ongoing debate about the role of eosinophils and their contribution to airway hyperresponsiveness in mice. There are significant differences depending on the sensitization and challenge protocol (16) and the parameter of airway function monitored (12). Eosinophil localization differs from strain to strain (17). Many studies defining critical pathways used genetically modified animals, knockouts, or transgenics. However, when targeted by antibodies or other inhibitors (i.e., conditional knockouts), different results are often encountered (18). The majority of studies emphasize results in a primary sensitization and challenge model where naive mice are sensitized and then exposed to a number of airway challenges. These protocols were used because they elicited a very strong immunoglobulin E response and airway eosinophilia. However, when compared with other protocols where initial sensitization and challenge is followed by a recovery period and then a single provocative allergen challenge is given, different cell types and mediators emerge and therapies that were obviously effective in the primary protocols are less effective (12). Overemphasis of results in the primary sensitization and challenge model has led to some confusion and perhaps the failure to translate to human disease. Finally, we have too often linked development of the T helper 2–like response to altered airway function in the mouse, a conclusion that itself is likely flawed. These may be two independent responses to sensitization and challenge that are not linked (19). In fact, a dearth of information on the molecular constraints of airway hyperresponsiveness in both mice and humans exists. These data all point to a heterogeneity in the murine system that is equal to the heterogeneity of human disease. Heterogeneity is evident at the genetic level, at the level of antigen-immune system interfacing, at the inflammatory cell response level, and even on the level of parameter of airway function monitored (12).

Airway inflammation and hyperresponsiveness are multigenic and multifaceted in mice and in humans. Insight gained in the murine models has fostered numerous avenues of investigation and identified numerous potential targets. The failure of this approach is hoping for the single magic bullet that remains elusive, rather than recognizing the need for additive/synergistic approaches, at least when targeting downstream events. There is now increasing attention to moving upstream in the immune/inflammatory cascade to achieve tolerance or immune deviation. In this approach, as in others, the murine models will provide a valuable tool for first assessing feasibility and then efficacy. But as human asthma is not likely a primary sensitization and challenge model, so too in the mouse efficacy must be established in previously sensitized/challenged hosts.

Humans remain the best model of human disease. As a surrogate, murine models have and will continue to play a prominent and important role in the evolution of our thinking. To quote Yogi Berra, "You can observe a lot just by watchin'!"

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