One of the paradoxes of modern medicine is the rapidly growing incidence of immune-based diseases over the last half of the century (1). Despite enormous advances in our understanding of the immune system, and our ability to manipulate immunity in experimental animals and man, we have not been able to curtail these diseases. In fact, it is becoming increasingly evident that immune hypersensitivity responses are central to the pathogenesis of many of the most common diseases of the 21st century including atherosclerosis, diabetes, obesity, and arthritis (2). Included in this epidemic are atopy-associated disorders (such as asthma, eczema, allergic rhinoconjunctivitis, and food allergies), which have skyrocketed during this time frame (about a threefold increase in prevalence). Currently, in the United States, nearly 30% of the population suffers from allergies with 5–10% suffering from asthma, a chronic inflammatory pulmonary disorder that is a chief diagnosis responsible for pediatric hospital admission, work and school absenteeism, and annual health care expenditures exceeding 12 billion dollars. While genetic factors certainly contribute to the pathogenesis of these diseases, there is emerging evidence that their rising incidence is related to changes in western lifestyle. For example, with increased time spent indoors (and its associated increased exposure to ubiquitous common antigens (derived from fungi, dust mites, and home pets), less exposure to rural outdoor adjuvants (eg, endotoxin from farm animals), increased use of antibiotics and vaccinations (and the associated changes in infections and endogenous flora), there is emerging evidence that the immune system has become “delinquent”, capable of eliciting the adverse responses associated with these disorders (3). Indeed, alterations in regulatory T cells (and TGF-β production) have been associated with these changes (4). Asthma is a disease defined by reversible airflow obstruction, and increased lung responsiveness to a variety of antigen-specific (allergens) and-nonspecific (eg, cold air, cigarette smoke) triggers, strongly associated with atopy (IgE production)(5). Histologically, the asthmatic lung is characterized not only by eosinophilrich inflammation, but also by a variety of chronic changes that induce lung remodeling (including mucus production, smooth muscle hyperplasia, and deposition of extracellular matrix components)(6). There is strong evidence that CD4+ T cells, especially of the Th2 phenotype, induce many of the features of asthma through the secretion of an array of cytokines (eg, IL-4, IL-5, IL-9, IL-13, and IL-25) that activate inflammatory and residential effector pathways both directly and indirectly (7). Notably, IL-4 and IL-13 directly trigger airway cells to undergo proasthmatic changes including production of mucus, expression of a variety of specific adhesion molecules (eg, ICAM-1 and VCAM-1), and production of a select sub-group of chemokines (eotaxins, macrophage chemoattractant proteins [MCPs]), and thymus–and activation–regulated chemokine [TARC]) that attract and activate allergic inflammatory cells (eg, eosinophils, macrophages, and Th2 cells)(8). The partial clinical effectiveness of glucocorticoids (agents that inhibit the production of Th2 cytokines, eosinophils, and T cells), cysteinylleukotriene (LT) inhibitors, and anti-IgE therapeutics indicates the critical interplay of multiple cells, cytokines, and mediators in disease pathogenesis.

Leukocyte migration into the allergic lung has been eloquently demonstrated to be dependent upon the coordinate interplay between selectins, adhesion molecules, and chemoattractant molecules (including chemokines and …