Targeting memory Th2 cells for the treatment of allergic asthma
Introduction
Allergic asthma is a chronic inflammatory disease of the conducting airways caused by an immune response directed against allergens. The syndrome affects both children and adults, resulting in loss of work and school days. It is responsible for numerous hospital visits, is a burden on the health system, and has important social and economic ramifications. Growing concern over the increase in incidence and prevalence in the last decades, in addition to increased morbidity and mortality associated with asthma, has intensified attempts to find new drug targets. Remarkably, the rise in incidence and prevalence of asthma in industrialized countries has not been adequately explained, and equally inexplicable is evidence showing that this trend is stabilizing (Lawson & Senthilselvan, 2005). Nevertheless, allergic asthma is a chronic, progressive illness, which is not influenced by diminished incidence rates. Moreover, certain patients are resistant to currently available drugs. The need for new and improved therapies is vital.
The best method of primary prevention for allergic disease is allergen avoidance. Environmental allergens, however, are impossible to elude; thus, the struggle to find improved treatments and cures persists. One strategy to cure disease is to prevent allergen sensitization, which currently is impossible because of our inability to determine susceptibility to allergic disease (atopy). Another approach is to suppress or eliminate memory CD4+ T helper (Th) 2 lymphocytes that mediate the allergic response and perpetuate allergic asthma. Th2 memory cells provide a valuable therapeutic focus in allergic asthma because of their specificity, which permits the treatment of disease without causing generalized immunosuppression.
Therapeutic strategies may be aimed at the prevention of disease or toward the inhibition of established disease. At present, it is difficult to construct novel treatments to inhibit disease initiation since the development of atopy cannot be predicted. New discoveries of genes associated with asthma, such as I-TIM1 (McIntire et al., 2004), arginase (Zimmermann et al., 2003), human thymic stromal lymphopoietin (TSLP; Soumelis et al., 2002), amongst other susceptibility genes (Hakonarson et al., 2002, Hytonen et al., 2004, Jinnai et al., 2004, Nicolae et al., 2005, Noguchi et al., 2005), however, may make it possible to establish reliable biomarkers that precede the manifestations of allergic disease. Thus, therapeutic strategies inhibiting the initial generation of memory Th2 cells must also be considered. Suppressing or eliminating Th2 cells will be most likely to ameliorate disease when the specific targeting of the approach is directed against the allergen receptor, Th2 cell, or memory Th cell. The latter 2 approaches tend to be broader and less specific than when the precise allergen is known and targeted. Inhibiting Th2 cells using non-allergen-specific methods is beneficial because the major role for Th2 immunity is in parasite defense, the loss of which is likely inconsequential in industrialized countries with few pathogenic parasites. However, inhibition of memory Th cells would cause immunosuppression, unless it was specific for memory Th2 cells. An additional consequence of Th2 suppression is a potential alteration of the balance between Th1 and Th2 immunity, leading to increased Th1 cells and autoimmunity.
Section snippets
Allergic immunity
Allergens are defined as substances that induce allergy. Common inhaled allergens are proteins derived, for example, from tree, grass and weed pollens, dust mites, molds, and animals such as dogs and cats. Ingested allergens are proteins found, for example, in seafood, peanuts, milk, and eggs. Exposure to allergens in susceptible individuals leads initially to allergen sensitization and the generation of CD4+ Th2 cells. Subsequent allergen encounters activate previously sensitized Th2 cells
Th2 cell generation
Why generate a Th2 immune response to allergens? In any battle, the main objective is to provide a first-rate defense while limiting collateral damage. Unfortunately, in the battle against pathogens, the immune system occasionally is either unable to adequately defend itself or causes unintentional harm by responding inappropriately. The immune system has evolved a defense mechanism for protecting against pathogens, which includes a strategy to avoid responding against innocuous, nonpathogenic
Immunological memory
Immunological memory is an important protective mechanism that enables host organisms to respond more rapidly and vigorously to pathogens that have been previously encountered. It is the reason why repeated infection with the same pathogen may not cause recurrent illness; it is also the basis of vaccine development. Immunological memory for bacterial and viral infections may be life saving, but, when directed against allergens, may cause morbidity and mortality. Memory immune responses are long
Targeting memory Th2 cells
The following sections will focus on the current paradigm of Th2 cell generation, activation, effector functions, and maintenance of immunological memory depicted in Fig. 2 and how it is possible to interfere with them to treat allergic asthma. It will begin with the initial encounter with allergen through to the processes that perpetuate Th2 cells and disease. The first step is allergen capture by APC and its subsequent handling and presentation, which converts a naive Th cell into an
Summary
Clinical studies and animal models have further elucidated a central role for Th2 memory cells in allergic asthma. The identification of functional pathways and genes associated with allergic asthma has had tremendous impact on the understanding of disease pathogenesis and drug discovery. The result has been specific strategies that exploit the unique properties of Th2 cells without concomitantly producing harmful immune responses or broad immunosuppression. A list of the most promising target
Acknowledgments
I would like to thank Drs. B. Mittleman, A. Baumgarten, P. Stuetz, and O. Hoffmann for their critical reading of the manuscript, discussions, and support.
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