A New Model for Understanding and Treating Asthma

Joel N. Kline, M.D.
University of Iowa Department of Internal Medicine
First Published: 2003
Last Revised: October 2003
Peer Review Status: Internally Peer Reviewed

History: Asthma in the industrialized world has increased in prevalence and severity for the past two decades. It is the most common chronic illness of children and has had a steady or rising mortality rate. One possible explanation for this phenomenon, which has spared underdeveloped nations, is the hygiene hypothesis.

The hygiene hypothesis proposes that various atopic (a.k.a., allergic) conditions, including asthma, are on the rise because of an imbalance caused by modern lifestyle between the Th1-type and Th2-type immune responses. Th1 responses are antimicrobial, whereas Th2 responses promote allergic reactivity. Th1 immune mediators include IL-12 and IFN-γ while Th2 cytokines include IL-4, IL-5, IL-9, and IL-13. These immune responses can balance one another, as Th2 mediators suppress Th1 responses and Th1 mediators similarly inhibit Th2 responses. Although both Th1 and Th2 responses are an important part of the immune system, and normal individuals may appropriately express Th1 or Th2 cytokines in certain settings (for example, Th2 responses are felt to play an important role in combating parasitic disease), people with allergies have an imbalanced Th2 response to otherwise harmless environmental proteins. Since children in modern society are exposed to fewer microbes and microbial products, they have fewer stimuli to develop Th1-type immunity; because of this, they may be at greater risk to develop imbalanced/polarized Th2 responses and allergic disease.

There are consistent epidemiologic data supporting the anti-allergic effects of early-life exposure to microbial antigens. For example, children who were raised on a farm (especially one where there was significant contact with livestock), or who have older siblings, or attended daycare at an early age (where they were exposed intensely to the common infectious diseases of childhood), or had early exposure to pet animals, have a significantly lower risk of developing asthma than children raised in the quasi-sterile conditions of an urban home. Adult farmers, despite a substantial respiratory burden from dusty work conditions, also are at a significantly lower risk for allergies than the general population. Tuberculin skin response has been shown to correlate with induction of Th1 cytokines and suppression of Th2 cytokines.

All these data support the idea that early life infections may protect against the development of atopic diseases like asthma. Thus, the hygiene hypothesis has provided an immunologic framework in which the balance between Th1 and Th2 immune responses is pivotal for the absence of atopic conditions.

However, another set of epidemiologic studies has shown that populations with high endemic levels of helminth infections (a potent natural stimuli for Th2 responses) appear to be protected against atopy. This suggests that an increase in Th2 responses alone is unlikely to explain the recent rise in atopic disorders. Moreover, the prevalence of diabetes type 1, a Th1-mediated disease, has also progressively risen in the same populations that have demonstrated an increase in atopic conditions. Thus, the concomitant increase in allergic disorders cannot adequately be explained by a reduction in Th1 responses.

New facts: The hygiene hypothesis, nevertheless, suggests two fundamental approaches to the treatment of asthma: the use of Th1 cytokines to counteract Th2 responses, or the direct suppression or blockade of interleukins that account for the Th2 responses. Both approaches result in a significant reduction of eosinophil cells, but neither has been proven to have a significant effect on airway hyperresponsiveness or allergen-induced bronchospasm. In other words, most of the attempted asthma therapies targeted on individual components of the allergic inflammation cascade have failed to demonstrate benefits for asthmatic subjects despite promising results in pre-clinical studies.

The failure of these approaches to treating asthma provides support for the assumption that the Th1-Th2 balance is controlled in a complex manner that cannot be altered by regulating individual components (e.g., a single Th1 or Th2 cytokine) of it. Moreover, recent data show that there is at least a third set of regulatory cytokines, produced by the T-regulatory cells, that is neither Th1 nor Th2 but controls both of these responses. Thus, the use of agents that suppress T-cell-mediated immune responses to allergens but do not globally impair immunity may be a more effective way of modulating asthmatic inflammation.

To date, corticosteroids remain the mainstay of anti-asthma therapy despite their potentially serious adverse effects. Although allergen immunotherapy is the only current treatment modality that has the potential to redirect the atopic inflammatory response, it has not been widely used in the treatment of asthma. Allergen immunotherapy is accepted for the treatment of atopic conditions, such as rhinitis and conjunctivitis. The reason for the infrequent use of allergen immunotherapy in asthma is that the risk of severe adverse effects is much greater in asthmatic than nonasthmatic allergic patients; this risk is dose-related, and significant in doses of immunotherapy that are potentially curative. The addition of stimulatory adjuvants to immunotherapy may enhance the utility of this modality by reducing the required dose of allergen and thereby reducing the risk of significant adverse effects.

In search of such an adjuvant, attention has turned toward bacterial DNA, which is known to be a strong inducer of Th1 response. Bacterial DNA differs from mammalian DNA in two key respects: a) bacterial DNA has the expected 1:16 frequency of CpG dinucleotides (cytosine and guanine with a phosphodiester backbone), while mammalian DNA has a 1:50 to 1:100 frequency, a clear CpG suppression; and b) the majority of the cytosines present in mammalian CpG dinucleotides are methylated, whereas they are not methylated in bacterial DNA. Oligodeoxynucleotides (ODN) containing sequence motifs positioned around nonmethylated CG dinucleotides (CpG ODN) have immune effects similar to those of native bacterial DNA. In addition to the strong induction of Th1 response, CpG ODN also strongly induce IL-10, which is associated with T-regulatory cells and is an inhibitor of both Th1 and Th2 responses in a dose-dependent manner. Thus, CpG ODN may inhibit Th2 responses through both the induction of Th1 response and the regulation of the Th1-Th2 balance (Fig. 1).

A promising model for asthma treatment: Based on the above understanding of the CpG ODN effects, a research group at UI Hospitals and Clinics has studied the possibility of using CpG ODN as a therapeutic option for allergic asthma. In clinical asthma, eosinophilic inflammation and bronchial hyperactivity are typically associated with Th2 responses. Inhalation of allergens such as pollens and dust mites leads to their ingestion and processing by airway mucosal dendritic cells. These cells present the allergen in the regional lymph nodes, whereby Th2 cells (prevailing in an atopic, sensitized individual) are stimulated to produce Th2 cytokines. The result of this is eosinophilia, allergen-specific IgE, and other manifestations of atopy. Mucosal exposure to microbial products, including bacterial DNA, promotes a Th1 response that suppresses the manifestation of atopy.

In a murine model of allergic asthma, we found that mice pretreated with CpG ODN developed significantly fewer lung eosinophils than mice that were sensitized in the absence of CpG ODN (Fig. 2). These mice were also protected against the development of peribronchial inflammation, bronchial hyperresponsiveness, and allergen-specific IgE. Generally, if an antigen was encountered in the context of CpG ODN, subsequent exposure to the antigen in the lung would be less likely to induce a Th2 response.

The clinical implication of our murine model is that respiratory mucosal exposure to CpG-rich DNA induces local immune responses that can inhibit atopic inflammation. Such tolerance-inducing responses are mediated through the induction and/or activation of dendritic cells as well as through regulatory T-lymphocyte populations. Another set of experiments led us to speculate that the efficacy of CpG ODN in allergy may depend on the promotion of regulatory responses as well as the induction of Th1 cytokines.

Since several autoimmune diseases are Th1 in nature, some speculated that CpG ODN might cause autoimmune conditions as a side effect. This was not the case in our murine model. Also, ongoing clinical trials have demonstrated mild flu-like symptoms in association with therapeutic response, but no autoimmune adverse effects.

In conclusion, CpG ODN can prevent sensitization and inhibit established Th2 response in an antigen-specific manner. CpG ODN exert their anti-allergy effects partially through Th1 cytokines and the regulatory cytokines IL-10 and TGF-β. Thus, CpG ODN may improve the safety and efficacy of immunotherapy, an established immunomodulatory treatment for atopic diseases.

Figure 1. Divergent outcome of T-helper Th0-type cells with allergen sensitization. Antigen-presenting cells in the lung, such as pulmonary dendritic cells (PDC), encounter the antigen in the lungs and migrate to the regional lymph nodes where they support the maturation of CD4+ helper Th0 cells to Th2. A: Mature Th2 cells migrate back to the lungs where they secrete Th2 cytokines and promote eosinophilic inflammation, increased IgE production, and mastocytosis. B: CpG ODN induce PDC to release IL-12, IL-18, IFN-γ, and TNF-α that promote maturation and skew lymphocytes toward Th1. CpG ODN also induce IL-10 that can suppress both Th1 and Th2 cytokines. The combined effect is a decreased production of IgE and reduced eosinophil survival.

Figure 2. Mice were sensitized to schistosome eggs (SEA), an experimental allergen, in the presence or absence of oligonucleotides (ODN), then challenged with SEA in their airways. A, E: normal control mice; B, F: asthmatic mice; C, G: asthmatic mice treated with CpG ODN; D, H: asthmatic mice treated with control (non-CpG) ODN. The significant eosinophilic inflammation and epithelial stimulation in the asthmatic mice (B, F) was markedly reduced by CpG ODN (C, G) but not by control ODN (D, H).

See related Provider Textbooks about Internal Medicine.

See related Provider Topics Asthma, Immune System/AIDS, Internal Medicine, Lungs and Breathing or Pulmonary.

See related Patient Textbooks about Internal Medicine.

See related Patient Topics Asthma, Immune System/AIDS, Internal Medicine, Lungs and Breathing or Pulmonary.

All contents copyright © 1992-2004 the Author(s) and The University of Iowa. All rights reserved.

http://www.vh.org/adult/provider/internalmedicine/treatingasthma/index.html