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American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 163-171, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.F276

Translational Review

Drug Development for Asthma

Michael J. Holtzman

Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

Address correspondence to: M. J. Holtzman, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: holtzmanm{at}msnotes.wustl.edu


   Abstract
Top
 Abstract
Introduction
 What's Being Done?
 Where Are Additional Needs?
 What Are the Alternative...
 References
 
Asthma is characterized by abnormal immune cell accumulation and activation in the airways as well as dysfunction of specialized parenchymal cells. Research strategies to define asthma pathogenesis have focused on the hypothesis that this altered state is a consequence of an excessive allergen-driven response. Drug development for asthma has been directed at improving existing agents and expanding new modalities that target the Th2 allergic cascade. Significant opportunities are being pursued in each of these areas. However, this strategy may not account for some critical aspects of asthma pathogenesis. Alternative considerations include the need for a multidisciplinary approach to dissect the complexity of the asthma phenotype as well as a better understanding of nonallergic factors (especially viral reprogramming of airway behavior) in the development of the phenotype. Each of these considerations may provide an alternative strategy for further drug development for asthma and other complex diseases.


   Introduction
Top
 Abstract
 Introduction
What's Being Done?
 Where Are Additional Needs?
 What Are the Alternative...
 References
 
Last week, I was the attending physician when a patient with severe asthma was admitted to the medical intensive care unit with respiratory failure. After several days of therapy that included glucocorticoids, bronchodilators, theophylline, and the latest antibiotics, the patient's condition showed little improvement. And then, as we all searched for how to proceed, it struck me that we had little more to offer this patient than we did at least 25 years ago. The pharmacologic advancements that had been made (e.g., improved formulations of ß2-adrenergic agonists and glucocorticoids, upgraded cromolyn-like agents, and even newly developed leukotriene antagonists and anti-IgE blocking antibodies) were of little use in this clinical situation. And, despite this patient's historical and physical findings of a viral bronchiolitis, we still had inadequate means to diagnose or treat that condition. After a quarter-century of active research and clinical enterprise, we were similarly frustrated in the treatment of patients with severe asthma. Here I will examine how this situation has developed and what can be done in the next period to achieve more significant progress in the treatment of asthma. Treatable asthmatic phenotypes (i.e., airway inflammation, hypersecretion, and hyperreactivity) are found in other acute and chronic airway diseases, and this issue will be addressed as well. In fact, asthma serves as a useful paradigm for understanding complex diseases in general.


   What's Being Done?
Top
 Abstract
 Introduction
 What's Being Done?
Where Are Additional Needs?
 What Are the Alternative...
 References
 
Let's begin by analyzing the current strategies for the development of new drugs for asthma. In that context, it appears that two prevailing themes dominate the approach to improving asthma treatment: (i) a pharmaceutical industry that prioritizes short-term time horizons and so aims to modify existing drugs in lieu of the longer and perhaps more difficult route of developing new agents; and (ii) a persistent focus on the possibility that some aspect of allergy is the main culprit for asthma pathogenesis and so should be the main target for research and development of new asthma therapy. This section will review these strategies, concentrating on some of the most widely adopted drug targets (summarized in general in Figure 1 and more specifically in Table 1). As noted previously (1–4) and further developed below, these strategies may not (by themselves) allow for significantly improved treatment.



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  		Figure 1. Traditional scheme for allergen-driven events that present anti-asthma drug targets. The scheme begins with initial (1°) allergen processing by dendritic cells and then MHC Class II restricted antigen presentation to T helper type 0 (Th0) cells that differentiate into Th2 cells. Under other conditions, Th0 cells may differentiate to Th1 cells or regulatory (Tr) cells. Under these conditions, Th2 cells then provide help for B cell production of IgE Ab. Subsequent (2°) allergen exposure may activate mast cells (via IgE-dependent Fc{epsilon}RI cross-linking) and Th2 cells (via MHC-dependent presentation to TCR and co-stimulation). These events then lead to activation of eosinophils. Each of these effector immune cell types release a variety of cytokines, eicosanoids, proteases, and other products that act on airway parenchymal cells (epithelial cells, myofibroblasts, and smooth muscle cells) to cause airway remodeling, hypersecretion, and hyperreactivity. Four general areas for therapeutic intervention (in boxes labeled 1–4) include: (1) allergen sensitization and IgE production, e.g., by allergen desensitization; (2) immune cell activation, e.g., by inhibition of specific cell surface receptors or downstream signaling events; (3) generation and/or production of immune cell products, e.g., by selective antagonists; and (4) altered parenchymal cell behavior, e.g., by modifying cell surface receptors, signaling, or gene expression. Additional details are provided in the text and Table 1.

 

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  		TABLE 1 New cellular and molecular targets and the concomitant approaches for asthma drug development

 
Modifying Existing Drugs
Perhaps the largest effort to modify existing therapies has been and continues to be the development of new glucocorticoid treatments. Considerable effort has been placed on the development of inhaled glucocorticoids with higher potency and selectivity as well as longer duration of action. In an extension of this strategy, new glucocorticoids are now also offered in combination with longer acting and more selective ß2-adrenergic bronchodilators. Initial data suggest that this combination (typified by fluticasone/salmeterol and budesonide/fomoterol) may provide synergistic effects that are greater than expected from the additive actions of either drug alone. Whether the efficacy of the combination is due to improved deposition of inhaled agents or to interaction of glucocorticoid and adrenergic receptor signaling at the cellular level is still uncertain. Additional research on the mechanism for possible synergy is needed to fully define whether it occurs and, if so, how. The effect of the combination on airway remodeling should also be studied further, because it may promote airway fibrosis (5). Long-term use of ß2-adrenergic agonists may also worsen underlying abnormalities in airway behavior, and this issue is also under study. Special concerns include the effects of ß2-adrenergic ligands (e.g., R- versus S-isomers) and ß2-adrenergic receptors (e.g., G{alpha}s versus G{alpha}q signals) on the levels of airway inflammation and hyperreactivity (6, 7).

It is noteworthy that a fixed combination of drugs was previously discarded as irrational, but such combinations are now projected to be the top-selling agents for asthma treatment. Higher efficacy of the combination drugs may be based at least in part on improved patient acceptance and compliance. As discussed below, compliance is a general problem that should be better monitored for both single and combination agents. In that regard, delivery systems that permit better monitoring and dosing are under development. For example, a smart system that senses an increased need for the bronchodilator component may automatically trigger additional delivery of the glucocorticoid component of the combination agent.

Another avenue for improvement in glucocorticoid action is aimed at designing new ligands that preserve efficacy in the airway while avoiding systemic side effects. This goal is especially applicable to the development of new glucocorticoids for inhalation. In particular, it may be possible to achieve selectivity using glucocorticoids that require bioactivation in the lung and do not exhibit systemic activity. In the case of ciclesonide, for example, the drug yields metabolites with 100-fold higher binding to the glucocorticoid receptor after activation in the lung (8). The active compound does not cause systemic side effects because a substantial fraction of the inhaled dose persists in the lung and the absorbed portion is highly bound to plasma proteins.

In another development for glucocorticoid design, the recent solution of the crystal structure of the glucocorticoid receptor ligand-binding domain revealed a novel mode of receptor dimerization and coactivator recognition (9). After activation by ligand, the glucocorticoid receptor translocates to the nucleus and binds to DNA promoter elements that can activate or repress gene transcription. In addition, glucocorticoid crosstalk with other transcription factors (e.g., nuclear factor-{kappa}B and activator protein-1) may repress their gene-activating properties. This repression may provide for anti-inflammatory and immunosuppressive activities, whereas distinct coactivation activities may lead to altered transcription that is responsible for side effects. Both repression and activation mediated by the glucocorticoid receptor require intact function of the ligand-binding domain, so these downstream effects can potentially be segregated at the level of receptor–ligand interaction. This new structure-function information may therefore provide a rational biochemical basis for the development of receptor ligands that trigger therapeutic but not side-effect signaling pathways. The use of selective gene targeting to generate cell-specific knockouts of the glucocorticoid receptor may also allow for better definition of glucocorticoid action. As developed below, this strategy will depend on the development of high-fidelity mouse models of asthma.

Th2 and Immunotherapy
Just as glucocorticoids serve as the prototype for modifying existing drugs, the ongoing attempts at immunotherapy exemplify the concentration on the Th2 hypothesis. This age-old approach stems from the premise that eliminating the initial trigger is the most effective means to avoid a subsequent response (i.e., allergen avoidance), and that dampening the response to the trigger is a compatible alternative (i.e., allergen immunotherapy). Furthermore, if asthma and allergy share common roots, then a rational goal of new asthma treatment is the development of immunotherapy that is designed to specifically downregulate the response to allergen or even create tolerance to it. Unlike anti-asthmatic (and anti-allergic) drugs, allergen-specific immunotherapy may attenuate symptoms for several years after it is discontinued. This approach therefore offers the possibility of disease modification rather than simple suppression.

Despite the clear rational for immunotherapy, the usefulness of this approach has been limited by the potential for adverse effects, particularly anaphylaxis, and the relatively crude nature of the allergen extracts that are available. To overcome these problems, revised strategies have been assessed in animals and are undergoing clinical evaluation. Naturally occurring isoforms of allergens from plants and trees have been shown to have a reduced capacity to be bound by IgE as a result of the substitution or deletion of amino acids (10). The use of hypoallergenic isoforms in immunotherapy may thereby minimize the risk of anaphylaxis. Similarly, the use of recombinant allergens should circumvent the problem of standardization of crude extracts by allowing production and purification of many of the major allergens in ways that eliminate variation between batches (11).

In addition, immunotherapy involving T cell peptide epitopes has been aimed at the administration of short, synthetic, allergen-derived peptides that induce T cell anergy or tolerance but, because of their short length, are unable to cross-link IgE and induce anaphylaxis. Early clinical trials in patients with allergy to cat dander showed that treatment with T cell peptides afforded limited protection against allergic symptoms induced by exposure to cats (12). The use of mixtures of allergen-derived peptides selected on the basis of their ability to bind to common major-histocompatibility complex class II molecules may have greater efficacy, because they will be recognized by T cells of most persons within a population (13, 14).

Th2 and DNA Vaccines
Another strategy aimed at downregulation of the allergic response is based on the development of DNA vaccines (15, 16). Plasmid vectors containing genes that encode allergens have been injected into animals, either before or after allergen challenge. This vaccine approach can markedly decrease Th2-mediated responses, enhance Th1-mediated responses, and suppress the allergic response. Virus-like particles can also induce interferon (IFN)-{gamma}–producing CD8+ T cells, rather than Th2-mediated responses (17). Another consideration is the induction of tolerance using mucosal DNA vaccination. For example, the main peanut allergen cloned into an expression vector when administered orally caused higher fecal IgA and serum IgG2a and lower serum IgE titers and resulted in a decreased anaphylactic response (18). Whether this approach or one directed at the airway mucosa would be efficacious for inhaled allergens still needs to be determined.

All of these efforts to downregulate the allergic response are tempered by the data that immunotherapy has shown only limited efficacy in treatment of asthma (19–21). In fact, a specific allergic trigger is difficult to define in many subjects with asthma. Furthermore, even in climates where allergic stimuli are reduced to a minimum, the disease does not remit. Perhaps for these reasons, alternative approaches have been devised to more generically decrease the Th2 response by enhancing the counteractive Th1 response. This strategy is further bolstered by the hygiene hypothesis for asthma, whereby a decrease in the normal level of Th1 responses may also contribute to allergic diseases (22, 23). Accordingly, strategies have been developed to broadly stimulate the Th1 response.

A particular approach for stimulation of Th1-mediated responses has been the administration of synthetic oligodeoxynucleotides with immunostimulatory sequences either alone or in combination with allergen (24). Strong immunostimulatory effects are driven by sequences containing unmethylated CpG motifs that are more highly represented in microbial than vertebrate DNA, and so are recognized as foreign by the innate immune system (often via Toll-like receptor 9). These motifs appear to function as Th1-promoting adjuvants capable of switching the usual Th2 response toward a Th1 response (25–27). Delivery of these drugs coupled to allergen in an adjuvant fashion or in combination with a glucocorticoid may also be considered to provide for longer lasting and more effective treatment. Preclinical results are promising, but the outcomes of clinical trials of these approaches for allergic rhinitis and asthma are still pending. Some experimental models suggest that interferons (especially IFN-{gamma}) or interleukin (IL)-12 (or other Th1 components) may mediate the observed efficacy. Because previous trials of these agents have not yet been effective in treating asthma (28–30), these cytokines and related targets will need to be monitored in future studies. As discussed below, at least some aspects of the vaccine approach must also be tempered by studies indicating that the Th1 response may augment the allergic and inflammatory response and that some elements of a heightened Th1 response may be characteristic of asthma (31–34). Another concern is that immunostimulatory agents have the potential for causing autoimmune disease after long-term administration.

IgE Inhibitors
Another Th2-based therapeutic approach is aimed at blocking IgE or its synthesis and so interrupting the allergic cascade. For example, treatment with a recombinant humanized monoclonal antibody (mAb) against IgE (Omalizumab) virtually eliminated IgE and markedly decreased the expression of Fc{epsilon}RI on basophils (35). In fact, a significant part of the therapeutic effect of this agent may depend on long-term downregulation of IgE receptors. Although the mAb neutralized IgE in blood, it did not activate mast cells, basophils, or monocytes, and so was not prone to cause anaphylaxis. Few side effects were observed in initial studies, but long-term studies are needed to assess the potential for immune-mediated consequences. The agent reduced symptoms of allergic rhinitis (36) and glucocorticoid usage in subjects with asthma (37). It also inhibited the allergen-induced early-phase and late-phase asthmatic reactions (38, 39). The degree of functional improvement and the safety of the treatment are still being defined, but initial results indicate some marginal benefit over inhaled glucocorticoids in severe asthma (40). These findings may be consistent with the development of experimental allergen-induced airway inflammation and hyperreactivity even in the absence of IgE (41).

Several additional approaches to inhibiting IgE biosynthesis and signaling are also under investigation. Based at least in part on the role of IL-4 in IgE generation, several strategies for inhibiting IL-4 have been evaluated. Treatment with soluble recombinant IL-4 receptor (to compete with endogenous ligand) moderately improved severe atopic asthma in an initial placebo-controlled trial (42). However, a subsequent large-scale trial indicated that this reagent had no clinical efficacy in asthma and the development of this project has been halted. Other approaches for blocking IL-4 receptor include administration of antibodies against the receptor and mutant IL-4 proteins (43). Interrupting downstream IL-4 receptor signaling by targeting transcription factors Stat6, GATA-3, or FOG-1 is also possible. Similarly, interruption of Fc{epsilon}RI signals by blocking its interaction with ligand or downstream signaling molecules such as Syk is also a possibility. Strategies directed against CD23 (Fc{epsilon}RII) are also in clinical trials. Enthusiasm for these approaches should not wane solely on the basis of negative results for IL-4 blockade, because the pharmacokinetics and the efficacy of each approach are distinct and somewhat unpredictable from experimental models.

Interestingly, late-phase allergic reactions can be induced in patients with atopic asthma in the absence of immediate hypersensitivity and attendant mast cell activation. Such reactions were induced in patients with asthma who were allergic to cats by an intradermal injection of peptides derived from a cat allergen (13). The fact that these late-phase reactions were independent of IgE and were MHC-restricted indicates that the activation of T cells alone is sufficient to initiate airway narrowing in patients with allergic asthma. The extent of this IgE-independent mechanism in asthma and allergic rhinitis still needs to be defined.

T Cell Costimulatory and Other Regulatory Molecules
Studies of experimental models of asthma have unequivocally defined the role of T cell costimulatory molecules (e.g., CD28 and CTLA4) in the development of allergic inflammation (44). The same studies, however, indicate that residual responsiveness to allergen may persist even after the loss of an individual costimulatory signal. Blocking more than one costimulatory pathway may be additive and so provides for a better therapeutic effect, but this higher degree of blockade can also result in compromised host defense (45). Significant progress has also been made in determining the pathways that regulate T cell differentiation. Although not completely defined, it appears that Th2 cell development is driven by IL-4/Stat6 control over GATA-3 and FOG-1 transcription factors, whereas Th1 cell differentiation is promoted by IFN-{gamma}/Stat1 control over T-bet transcription factor (46). Additional checkpoints for Th1 cell development include expression of IL-12ß2 receptor and production of IL-12 and IL-18 versus IL-10. An initial report indicates that decreased expression of T-bet in CD4+ T cells may be characteristic of asthma, although this report did not assess Th2 status (47). In addition, it appears that T-bet may not influence CD8+ T cells (48), and these cells may also be important for the asthma phenotype (49, 50). Whether the behavior of any of these transcription factors in T cells primarily mediates asthma pathogenesis remains uncertain. To define this issue, the pharmacologic means to modify the function of these transcription factors (or any others) still needs to be developed and then applied to human subjects.

Additional Anti-Th2 Efforts
By defining events downstream of allergen-triggered activation of T cells, additional drug targets in the Th2 cascade have been identified. These targets are also largely derived from experimental work in mouse models of asthma using allergen sensitization and challenge and then extrapolated to allergen challenge and the delayed response to allergen in humans (51). For example, IL-5 was proposed as a key ingredient in experimental mouse models and a consequent target in humans. In fact, in monkeys with ascaris-induced asthma, a mAb against IL-5 almost completely eliminated eosinophilia and airway hyperresponsiveness (52). A recent study in patients with mild asthma showed that a high-affinity humanized IgG1 mAb against IL-5 abolished eosinophils in blood and reduced the number of eosinophils in sputum, but had no apparent effect on the allergen-induced late-phase asthmatic reaction or nonspecific airway hyperreactivity (53). At least three follow-up studies also showed no significant effect of treatment with anti–IL-5 mAb on asthma symptoms and airway obstruction, but treatment did not completely eliminate sputum or tissue eosinophilia (54). Long-term studies that more effectively eliminate tissue eosinophils will be required to establish the role of eosinophils and IL-5 in chronic allergic disease and asthma. It therefore remains possible that combining anti–IL-5 strategies with agents that inhibit eosinophil chemotaxins (e.g., an anti-eotaxin) may be more effective for anti-asthma treatment.

Another strategy has been the development of agents that block the pathways triggered by IL-13. Experimental work indicates that IL-13 signals via the IL-13R{alpha}1 receptor chain, and this signal can be blocked by competition with an engineered form of the non-signaling IL-13R{alpha}2 (i.e., soluble IL-13R{alpha}2-IgGFc fusion protein) (55). In models of allergen challenge, this reagent blocks IL-13–dependent induction of hyperreactivity, goblet cell metaplasia, and subepithelial fibrosis (56). However, other reports indicate that IL-13 may not be required for these phenotypes under all conditions. For example, IL-9 may cause goblet cell hyperplasia using a pathway that does not require IL-13 (57). In addition, the asthma phenotype can be triggered in experimental settings such as respiratory viral infection, where IL-13 does not appear to be expressed (58). Clinical trials of IL-13 blockade will soon be completed to better define its role in asthma pathogenesis.

Because monomeric soluble receptors (e.g., soluble IL-4R{alpha}) often exhibit low affinity or partial agonist function, other methods for blocking cytokine action are also under study. One example has been the development of high-affinity blockers (cytokine traps) that consist of fusions between the constant region of IgG and the extracellular domains of two distinct cytokine receptor components involved in binding the cytokine (59). Initial results indicate that an IL-4 trap with IL-4R{alpha}/IL-2R{gamma} components can effectively block ovalbumin-induced eosinophil influx in mice, and initial experiments with IL-4R{alpha}/IL-13R{alpha}1 indicate high-affinity blockade of IL-4 and IL-13 signaling. Presumably, additional testing is underway to determine efficacy in other in vivo models and in humans.

Other strategies for reducing the allergic response are aimed at the controls over the influx of immune cells (especially eosinophils) into the airway tissue. Suitable targets for inhibition include the {alpha}4ß1-integrin (VLA-4) that serves as the receptor for vascular cell adhesion molecule 1 (VCAM-1), CCR3, the CC chemokine receptor on eosinophils and mast cells that binds eotaxin, as well as other chemokine–chemokine receptor interactions (e.g., CCL17/CCL22-CCR4, CCL1-CCR8, and CXCL12-CXCR4) that may be selective for Th2-related events and asthma (60–63). Each of these strategies is being pursued, as well as dual-action agents that may target more than one cell adhesive interaction. Initial communications have indicated little efficacy of anti–VLA-4 mAb in asthma despite success in other inflammatory conditions (64). Although improved delivery of this agent to the airway tissue may increase its efficacy, it is also possible that the poor outcome reflects a lack of attention to the added nonallergic component that is critical for asthma. Thus, it is still possible that these types of treatments will be more effective in allergic rhinitis where IgE-dependent allergic responses may be the dominant mechanism for pathogenesis.

Additional Anti-Inflammatory Agents
Based on the hypothesis that inflammation (allergic or otherwise) is critical to the development of asthma, the disease might best be controlled by targeting specific inflammatory components. In that context, the activity of mast cells has been proposed as a critical component of asthma pathogenesis, and specific antagonists have been developed to downregulate the activity of mast cell proteases (e.g., tryptase) and lipid mediators (e.g., LTD4 and PGD2). Trials are still underway to test an orally taken antagonist of tryptase. Recent recognition of a second PGD2 receptor (CRTH2) that mediates inflammation has led to the development of specific antagonists for this receptor. Some agents (e.g., Ramatroban) that block thromboxane receptors also inhibit CRTH2, and some nonsteroidal anti-inflammatory drugs (e.g., indomethacin) inhibit prostaglandin synthases but are partial agonists of CRTH2 (65). Thus, the specificity of these agents will need to be monitored. Additional work aims to determine the effects of a phosphodiesterase type 4 (PDE4) inhibitor in asthma and COPD (66). These agents are reported to provide bronchodilating and anti-inflammatory effects, but gastrointestinal (emetic) side effects have been problematic in some agents in this class. Each of these strategies will also need to account for evidence that asthma is distinguished by mast cell infiltration of airway smooth muscle, and this myositis is composed of mast cells from the tryptase/chymotryptase-positive subset (MTC) with a distinct a distinct profile of inflammatory actions (63, 67).


   Where Are Additional Needs?
Top
 Abstract
 Introduction
 What's Being Done?
 Where Are Additional Needs?
What Are the Alternative...
 References
 
Taken together, current therapies have provided reasonable efficacy for treatment of mild asthma. In this group (and in more severe disease), there is still a critical need to make these therapies readily available to patients and to educate patients as to how and why the medication must be taken on a regular basis. In general, patients are reluctant to acknowledge that treatment must be continued during asymptomatic periods to fully suppress inflammation and to prevent recurrence. The general lack of physician and patient attention to this area of treatment delivery remains at a high level, and progress in education of care providers and receivers with a consequent improvement in compliance is still needed.

However, these issues beg the question of how to provide better drugs for asthma. Existing therapies even when given appropriately do not fully solve the clinical problems of subjects with moderate and severe asthma. Under current treatments, these patients still experience significant residual symptoms and are still subject to frequent exacerbations of their disease that can be life threatening. Even under the best of circumstances, these individuals remain dependent on continuing medication and the attendant anxieties and consequences of long-term treatment with glucocorticoids. In that regard, all classes of subjects with asthma would be aided by the development of agents that modify the disease rather than simply altering or suppressing the phenotype on a temporary basis. Glucocorticoids are often cited as agents capable of disease modification, but even in this case, cessation of treatment causes full recurrence of the phenotype, sometimes in a more severe form. Allergen desensitization or suppression of allergy by downregulating IgE-dependent events might also be viewed as disease-modifying approaches. But, as noted above, these modalities have so far been capable of only limited efficacy. In fact, the next section will develop the possibility that nonallergic mechanisms may be a major factor in the pathogenesis of asthma, so even full and effective treatment of allergy may still not improve disease outcome.

Asthma represents a paradigm for a complex disease that requires a multidisciplinary, translational approach. Nonetheless, most past and present strategies for defining asthma pathogenesis and identifying new drug targets have been narrowly directed. Consider the particular focus of asthma research on genetic susceptibility to developing the disease, where the initial approach was almost entirely confined to candidate genes with a role in the allergic response. Since then, experimental models have defined linkage of asthma phenotypes to previously unsuspected gene candidates (e.g., complement components C3a receptor and C5), and genome-wide screens in human populations have identified linkage with unrecognized metalloproteinases (e.g., ADAM33) (68–70). However, even in these cases, there was little linkage between observations in experimental models and findings in human subjects, and there remained significant doubt over functional significance in both systems. Despite at least ten years of support for a network of genetic research, there is still no universal agreement on any susceptibility gene for asthma. Nonetheless, pharmacologic strategies to target the products of the available candidate genes are already into clinical trials.


   What Are the Alternative Strategies?
Top
 Abstract
 Introduction
 What's Being Done?
 Where Are Additional Needs?
 What Are the Alternative...
References
 
The first alternative in thinking about asthma is to consider that common diseases in general and asthma in particular are likely to be multifactorial and multigenic. In addition, the lung exhibits a limited set of responses, so there is significant overlap in the phenotype that is observed among different diseases. This complexity poses significant challenges for developing complete and accurate models of lung disease that can be used for understanding pathogenesis, and in particular for the current emphasis on genetic and genomic analysis. Nonetheless, a multi-layered strategy that includes in vitro and in vivo systems can offset these limitations. In addition, several tools (e.g., endobronchial biopsy or brushing, bronchoalveolar lavage, and new imaging techniques) and new protocols (e.g., glucocorticoid withdrawal) can directly monitor the endogenous behavior of the human airway. A well-coordinated assessment of representative in vitro systems, animal models, and human subjects has rarely been taken but represents a significant strength in approaches to complex lung diseases.

The second alternative in asthma thinking is to consider that several lines of evidence in model systems and in humans raise questions about the role of allergy and the corresponding Th2 bias as a sole explanation for asthma. For example, antigen-specific Th2 cells are not sufficient for initiating the asthmatic phenotype in experimental models of allergy (34) and conversely, the phenotype may develop without notable allergic components, such as IgE production or eosinophilic inflammation (56, 71, 72). Perhaps these disconnects should not be surprising, because in human subjects the development of allergy and asthma are often dissociated as well (31), and linkage to candidate genes for atopy may be absent in large segments of subjects with asthma (73). Moreover, as summarized above, treatment aimed at selective blockade of Th2 pathways has not yet proven to be efficacious in asthma (2). These discrepancies are generally ascribed to the complexity of the allergic response. Even given this diversity, however, an allergen-based proposal for pathogenesis provides little explanation for at least two major features of the asthma phenotype: first, an invariant and persistent abnormality in airway epithelial programming toward an anti-viral response that reflects a Th1 bias (32, 33, 74), and second, in a related manner, the development of a chronic (likely permanent) asthma phenotype in the face of a relatively short-term allergic response (58).

The features of epithelial re-programming, chronicity, and susceptibility in asthma have led to an alternative paradigm for asthma pathogenesis that includes epithelial, viral, and allergic (epi-vir-all) components (1). Indeed, we now recognize that, at least experimentally, viral infection can certainly lead to a chronic asthma phenotype in a suitable genetic background (4, 58). The teleology of this chronic response is uncertain, but it may represent an evolving but maladaptive attempt to improve antiviral host defense. In that regard, more difficult and newer strains of respiratory viruses (with more dynamic genomes) rather than significant changes in host behavior might best explain the increasing incidence of asthma. This process could work in concert with immunization strategies as well as other forces that increase pressure on the allergic phenotype. Further studies will need to determine whether this paradigm serves to explain the link between paramyxoviral infection in infancy with subsequent asthma in childhood and perhaps adulthood. Nonetheless, these observations already create a powerful approach for establishing linkage of individual aspects of the complex asthma phenotype to distinct DNA elements that confer genetic susceptibility (Figure 2). In addition, a new set of immunologic questions, analogous to those already posed for allergen-driven disease, now arises for virus-driven asthma. These new queries include defining the nature of the viruses that confer the asthma phenotype as well as the host cell populations and corresponding factors that initiate, memorize, and effectively translate this memory into the asthma phenotype (Figure 3). Each of these issues provides new seeds for drug development. Moreover, the viral pathway appears genetically and immunologically distinct from the one for allergy, thereby providing an alternate route for driving the development of new disease-modifying drugs for asthma. Combined attention to both of these overlapping but distinct pathways to asthma pathogenesis is therefore likely to yield more effective treatments for asthma and related conditions that are characterized by airway inflammation, hypersecretion, and hyperreactivity.



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  		Figure 2. Schematic approach to defining the genetic basis of complex lung diseases. This scheme begins with (1) characterizing disease traits in human subjects (uppermost box) and proceeds clockwise through (2) developing a mouse model that exhibits the same disease trait; (3) defining parental strains that do or do not exhibit the trait but are otherwise well-matched for other traits; (4) generating genetic hybrid strains that exhibit a broad distribution of the same phenotypic trait, e.g., an F2 intercross; (5) performing a whole genome scan, e.g., using allele-specific SNP markers, on phenotypic extremes to identify loci that are linked to the trait; (6) identifying specific candidate genes at the locus either by finer mapping and sequencing or screening for altered gene expression by oligonucleotide microarray; (7) defining the function of the new candidate gene using a mouse model that exhibits expression of the corresponding trait in vivo and if possible in vitro to better establish molecular mechanism; (8) returning to human subjects to check for altered expression and/or function of the candidate gene to the extent that is possible in research on humans, especially in relationship to the trait under study (1). Modified from Ref. 51.

 


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  		Figure 3. Scheme for parallel allergic and viral cascades for asthma pathogenesis and the research gaps in defining the virus-driven events. A illustrates how allergen, in genetically susceptible individuals, is processed by antigen-presenting cells (APCs) and then leads to the involvement of B cells and Th2 cells and subsequent activation of mast cells and eosinophils. These events combine to cause alterations in end-organ cells (e.g., goblet cells and airway smooth muscle cells) to cause the asthma phenotype (e.g., mucus hypersecretion and airway hyperreactivity). B illustrates how viral replication, in susceptible individuals, can first activate host initiator cells (e.g., airway epithelial cells, macrophages, and dendritic cells), and then lead to the generation of memory cells (e.g., B cells and T cells) and consequent activation of effector cells (e.g., virus-specific T cells and mast cells) to cause end-organ alterations that are characteristic of asthma. Allergen- and virus-driven pathways appear at least partially sensitive to downregulation by glucocorticoid (GC) at the initial as well as subsequent steps, but the allergic response appears selectively sensitive to inhibition by IFN-{gamma}. Each of the steps in the viral pathway (including the nature of the virus) needs to be more completely defined as outlined in the text.

 

   Acknowledgments
 
The author gratefully acknowledges his colleagues for invaluable assistance, advice, and information and the National Institutes of Health (Heart, Lung, and Blood Institute), Martin Schaeffer Fund, and Alan A. and Edith L. Wolff Charitable Trust for research support.

Received in original form May 7, 2003


   References
Top
 Abstract
 Introduction
 What's Being Done?
 Where Are Additional Needs?
 What Are the Alternative...
 References
 

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