Asthma is a significant chronic health problem in the U.S. and other developed nations. It accounts for millions of hospitalizations and thousands of deaths per year. The incidence of this burdensome ailment has increased by 50% every ten years raising the prevalence in the U.S. to 26.7 million in 1997 [1, 2].
A significant disparity in new asthma diagnoses has been noted between urban and suburban/rural children. Urban children suffer a significantly higher incidence of asthma than their non city-dwelling counterparts . This effect has been attributed to differences in exposure to sensitizing allergens present in the environment. Namely, it is theorized that an allergen(s) present at higher concentration, or in a unique combination in urban environments is the principal aggravating factor. Suspected allergens include feline, canine, murine, dust mite and cockroach allergen and pollutants such as diesel particulates.
A landmark paper published in 1997 identified a link between asthma incidence in urban children and antigens derived from the ubiquitous pest Blattella germanica, the German cockroach . This link was further investigated in 1998 by the development of the first cockroach allergen induced model of asthma . Publications from this lab have shown that aqueous house dust extract from the kitchens of severely asthmatic, urban children can induce allergic asthma-like symptoms in mice. Moreover, the most potent and abundant allergens identified in the dust extract were proteins of the German cockroach . Thus, the study of cockroach allergen as an inducer of asthma in mice and humans is a rational first step in untangling the complex web of environmental exposure and allergic asthma.
Despite the alarming increase in prevalence and incidence of asthma in recent times, treatments have evolved slowly. Current standards of care include a long lasting anti-inflammatory agent such as an inhaled glucocorticoid or long acting β2 adrenergic agonist, combined with a short acting β2 agonist rescue inhaler and or epinephrine injections. Other effective agents include anti-IgE monoclonal antibodies, leukotriene receptor antagonists, mast cell degranulation inhibitors, antihistamines and cholinergic antagonists [1, 6, 7]. These treatments focus on alleviating the symptoms of the disease rather than addressing the cause. Specifically, they manipulate events occurring downstream of the aggravating stimulus to diminish certain aspects of the response. While these drugs are very effective at decreasing exacerbations and halting attacks, they tend to lose effectiveness over time. Asthma progresses because chronic, inflammation-induced lung remodeling coupled with drug desensitization, allow the disease to become more severe and recalcitrant to treatment over time.
Allergen desensitization is thus a highly attractive option for the treatment of allergic-type inflammatory diseases. This form of treatment has a significant advantage over standard therapeutic agents in that it addresses the fundamental cause of asthma rather than modifying downstream mediators. In addition allergen desensitization has the advantage of being tailored to the individual patient. A skin hypersensitivity panel can be performed for a wide array of potential allergens in order to identify the causative agent(s). Thus, the desensitization regimen can be narrowly focused on the most likely causative allergens, offering symptomatic relief based on rational and specific treatment targeted to the inciting allergens(s).
Current desensitization procedures deliver increasing titers of the putative allergen subcutaneously over a period of weeks. The patient must travel to their physician's office and remain in the clinic for 30 minutes after the injection in case a life-threatening reaction occurs. In addition, the administering health professional must be specially trained and have the capacity to treat severe anaphylaxis [8, 9]. These factors make current desensitization procedures relatively costly and inconvenient for both the patient and the care provider.
Sublingual/oral allergen desensitization is starting to gain wider interest and acceptance[10, 11] with significant advantages over subcutaneous desensitization. Chief among these is the lower potential for anaphylaxis. The patient is monitored for severe reactions only after the first dose; subsequently, he/she can self-administer treatment in their own home. This vastly increases compliance as there is very little disruption of the patient's daily schedule. This is especially true for asthmatic children in whom compliance is a significant issue. Therefore, oral desensitization is an ideal candidate for the treatment of allergic type asthma.
Although oral tolerance is gaining wider acceptance, the mechanism of how this occurs has not been determined. We designed studies to examine whether oral tolerance would effectively relieve asthma-like pulmonary inflammation in response to cockroach allergens, and determine the mechanism(s) of why oral tolerance is effective.