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Review
. 2010 Feb 16;152(4):232-7.
doi: 10.7326/0003-4819-152-4-201002160-00008.

Narrative review: the role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes

Stewart J Levine  1 , Sally E Wenzel
Affiliations
Review

Narrative review: the role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes

Stewart J Levine et al. Ann Intern Med. .

Abstract

New therapeutic approaches are needed for patients with severe asthma who are refractory to standard therapy comprising high doses of inhaled corticosteroids plus long-acting beta(2)-agonists. Current treatment guidelines for patients with severe asthma from the National Asthma Education and Prevention Program recommend the addition of oral corticosteroids, which are associated with substantial morbidity, and, for those with allergic asthma, anti-IgE. Genetic and translational studies, as well as clinical trials, suggest that in a subgroup of patients, the pathobiology of severe asthma is mediated by immune pathways driven by T-helper 2 (Th2)-type CD4(+) T cells, which produce a characteristic repertoire of interleukins (ILs), including IL-4, IL-5, and IL-13. Therefore, biological modifiers of Th2-type ILs, such as monoclonal antibodies, soluble receptors, and receptor antagonists, are a rational strategy for developing new treatment approaches but will need to be targeted to selected patients in whom the appropriate Th2 immune pathway is "active." The benefits of immune-modifier therapies targeting Th2-type cytokines, however, need to be weighed against the toxicities associated with inhibition of key biological pathways, as well as the expense of future medications. Therefore, future clinical trials need to clearly establish the efficacy and safety of biological modifiers of Th2 immune pathways before these approaches can enter routine clinical practice for the treatment of severe asthma.

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Conflict of interest statement

Potential Conflicts of Interest: Dr. Levine is the holder of a patent entitled, “Regulators of type-1 tumor necrosis factor receptor and other cytokine receptor shedding,” U.S. Patent # 7,135,303. Dr. Levine also has a patent application pending entitled, “TNF-alpha converting enzyme inhibitory agents and stimulatory agents.”

Dr. Wenzel has received consulting fees from Centocor and was Chair of the Steering Committee for the Anti-TNF trial in severe asthma. She has received consulting fees from Genentech and Novartis in relation to treatment of severe asthma. She has consulted for GlaxoSmithKline, Wyeth, Amgen, and Altair. She serves on the Scientific Advisory Board for Altair. Dr. Wenzel has received grants from GlaxoSmithKline, Ception, Medimmune and Aerovance.

Figures

Figure 1
Figure 1. Stepwise approach for managing asthma in youths greater than 12 years of age and adults as recommended by the Expert Panel 3 of the National Asthma Education and Prevention Program(4)
Therapy should be increased to the next step if symptoms are not well controlled or poorly controlled, as indicated by the use of short-acting β2-agonists or the presence of asthma symptoms more than 2 days per week, nighttime awakenings due to asthma symptoms at least once per week, some interference with normal activities, or a reduction in FEV1 or peak flow below 80% of predicted or personal best. Allergen immunotherapy may be considered for patients at steps 2 – 4, especially those with single allergies to house-dust mites, animal danders or pollens. Health care providers should be prepared to identify and treat anaphylaxis that can be associated with immunotherapy and omalizumab. All patients should receive education, environmental control and management of co-morbidities. If asthma is well controlled for at least 3 months, then therapy should be decreased downward to the next step. Abbreviations are as follows: ICS (inhaled corticosteroids), LABA (long-acting β2-agonists), LTRA (leukotriene receptor antagonists), and SABA (short-acting β2-agonists).
Figure 2
Figure 2. Modulating Th2 immune pathways for the treatment of asthma
An early step in the initiation of allergic airway inflammation is the activation and maturation of antigen-presenting dendritic cells in response to thymic stromal lymphopoietin (TSLP), an interleukin-7-like cytokine that is produced by airway epithelial cells, fibroblasts and mast cells. Mature dendritic cells induce the differentiation of naïve CD4+ T cells into Th2 cells, which produce a characteristic repertoire of cytokines, such as IL-4, IL-5, IL-9, IL-13, as well as tumor necrosis factor (TNF). Th2 cytokines mediate airway eosinophil and mast cell recruitment, B cell IgE isotype class switching, and mucus secretion. Dendritic cells also secrete IL-6, which plays an important role in the differentiation of both Th2 and Th17 cells. IL-17, which is produced by Th17 cells, mediates airway neutrophilia by inducing the production of CXC chemokines, which are chemoattractant factors, and granulocyte-colony stimulating factor (G-CSF), a survival and proliferation factor, by bronchial epithelial cells. IL-17 also induces mucin gene expression. Regulatory T cells (Tregs) negatively regulate immune responses via the production of IL-10 and transforming growth factor-β (TGF-β).
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