Immunotherapy in Asthma

Richard Warrington

Disclosures

Immunotherapy. 2010;2(5):711-725. 

In This Article

Abstract and Introduction

Abstract

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. Chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, as well as variable airflow obstruction within the lung. With time, such airflow obstruction may become permanent due to remodeling. It has been treated for more than 100 years by subcutaneous immunotherapy with allergen extracts but in recent years, other forms and types of immunotherapy have been introduced. Perhaps the most successful of these to date, is sublingual immunotherapy, which has attained significant usage in European countries but has yet to make inroads into clinical practice in North America. Other mechanisms to modify the inflammatory responses of asthma have included immunotherapy with recombinant allergens, the use of allergen peptides targeting antigen-specific T cells and the administration of Toll-like receptor agonists coupled to allergen proteins. As the inflammatory responses in asthma frequently involve IgE, a modified monoclonal antibody to IgE and interfering with its binding to the IgE receptor have gained acceptance for treating severe allergic asthma. Other monoclonal antibodies or recombinant receptor antagonists are being assessed for their ability to block other contributors to the inflammatory response. Finally, attempts have been made to generate autoantibody responses to cytokines implicated in asthma. Most of these therapies aim to modify or inhibit the so-called Th 2 immune response, which is implicated in many forms of asthma, or to inhibit cytokines involved in these responses. However, an added benefit of classical immunotherapy seems to be the ability to prevent the allergic progression to new sensitivities and new forms of allergic disease.

Introduction

It is currently perceived that there is an asthma epidemic.[1] In North America, allergic diseases affect approximately 20% of the population and are the third and fifth leading causes of chronic disease in children and adults, respectively.[2] While current therapies include allergen avoidance and medications such as antihistamines, leukotriene receptor antagonists and corticosteroids, for almost 100 years, vaccination or immunotherapy has been practiced to control the development of allergic symptoms that occur on contact with allergen.

Asthma is characterized in large part by an abnormally polarized Th-2-type immune response, often specific for innocuous allergens. This results in an inflammatory response that has been hypothesized to be responsible for the persistent changes of airway remodelling (Figure 1). This proposal is now being questioned with more attention paid to the active epithelial mesenchymal trophic unit that is activated during tissue injury and repair. The damaged lung epithelium expresses increased levels of arginase, which reduces bronchodilatory and antiproliferative nitric oxide (NO) and promotes the release of amino acids and polyamines regulating smooth muscle remodeling. The airway smooth muscle itself actively participates in the process through the secretion of chemokines and cytokines.[3–5]

Figure 1.

Allergic response and potential sites for modulation.
LTC4: Leukotriene C4; PGD: Phosphogluconate dehydrogenase; SCIT: Subcutaneous immunotherapy; TCR: T-cell receptor; TLR: Toll-like receptor; Treg: Regulatory T cell.
Adapted with permission from [158].

While the mechanisms of action of immunotherapy were initially unknown, in the last 40 years, the immunopathology of allergic disease has become better understood and this has allowed the development of new forms of immunotherapy that target specific molecules involved in the causation of diseases such as asthma. In addition, the use of classic immunotherapy has become more sophisticated, with the introduction of alternative methods of administration and new forms of allergen. It is these modalities that are the subject of this article.

Therefore, immunotherapy in asthma may now include subcutaneous immunotherapy, sublingual immunotherapy (SLIT), treatment with specific monoclonal antibodies against IgE, TNF, IL-5, Toll-like receptor (TLR)-9 vaccines, cytosine phosphorothioate guanosine (CpG)–allergen conjugates, allergen peptide vaccines and even vaccines generating autologous antibodies to specific cytokines such as TNF and IL-5.

The importance of immunotherapy in asthma lies not only in its ability to modify ongoing disease processes but also in its potential to prevent progression of allergic disease.

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