Stewart J. Levine, MD; Sally E. Wenzel, MD
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 Î²2-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)â€“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 â€œactive.â€ 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.
Steps as recommended by the Expert Panel Report 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 are very poorly controlled, as indicated by the use of short-acting β2-agonists or by 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 to 4, especially those with single allergies to house dust mites, animal danders, or pollens. Health care providers should be ready to identify and treat anaphylaxis that can be associated with immunotherapy and omalizumab. All patients should receive education, environmental control, and management of comorbid conditions. If asthma is well controlled for at least 3 months, then therapy should be decreased downward to the next step. ICS = inhaled corticosteroids; LABA = long-acting β2-agonists; LTRA = leukotriene- receptor antagonists; PRN = as needed; SABA = short-acting β2-agonists.
An early step in the initiation of allergic airway inflammation is the activation and maturation of antigen-presenting dendritic cells in response to TSLP, an IL-7–like cytokine that is produced by airway epithelial cells, fibroblasts, and mast cells. Mature dendritic cells induce the differentiation of naive 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 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. Interleukin-17, which is produced by Th17 cells, mediates airway neutrophilia by inducing the production of CXC chemokines, which are chemoattractant factors, and G-CSF, a survival and proliferation factor, by bronchial epithelial cells. Interleukin-17 also induces mucin gene expression. Tregs negatively regulate immune responses via the production of IL-10 and TGF-β. G-CSF = granulocyte colony-stimulating factor; TGF = transforming growth factor; TNF = tumor necrosis factor; Treg = regulatory T cell; TSLP = thymic stromal lymphopoietin.
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Medical Service, Comando Brigata alpina Julia, Udine, Italy
March 2, 2010
The immunomodulatory properties of vitamin D and asthma.
Levine and Wenzel (1) reviewed the role of T-helper 2 (Th2) immune pathways in the pathogenesis of subgroups of patients with severe asthma, and proposed biological modifiers of Th2 immune pathways as a rational approach for developing new treatments for severe asthma that could be added when standard therapies do not provide adequate control. We suggest that, in this setting, the immunomodulatory properties of vitamin D may have a fundamental action. Modulation of the immune system is one of the principal roles of vitamin D, for which the effects are exerted via the vitamin D receptor (VDR). Multiple immune cell types express VDRs, including activated T and B cells, macrophages and dendritic cells. In particular, vitamin D modulates the Th2 response affecting cytokines (2). Indeed, it has been shown that in asthma, reduced vitamin D levels are associated with impaired lung function, increased airway hyperresponsiveness and reduced glucocorticoid response (3). Furthermore, in experimental animals, topical 1,25-dihydroxyvitamin D3 increased the immunoregulatory capacity of CD4 CD25 regulatory T cells, which in turn could modulate Th2 driven immune responses in a mouse model of asthma (4). Finally, it has been found an association between VDR variants and asthma (5). Therefore, adequate levels of vitamin D should be reached in all patients with asthma in order to improve multiple parameters of asthma severity and treatment response.
1. Levine SJ, Wenzel SE. Narrative review: the role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes. Ann Intern Med 2010; 152: 232-7.
2. Lange NE, Litonjua A, Hawrylowicz CM, Weiss S. Vitamin D, the immune system and asthma. Expert Rev Clin Immunol 2009; 5: 693-702.
3. Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DY. Vitamin D levels, lung function and steroid response in adult asthma. Am J Respir Crit Care Med 2010 Jan 14. [Epub ahead of print]
4. Gorman S, Judge MA, Burchell JT, Turner DJ, Hart PH. 1,25- dihydroxyvitamin D(3) enhances the ability of transferred CD4( ) CD25( ) cells to modulate T helper type 2-driven asthmatic responses. Immunology 2010 Jan 6. [Epub ahead of print]
5. Saadi A, Gao G, Li H, Wei C, Gong Y, Liu Q. Association study between vitamin D receptor gene polymorphisms and asthma in the Chinese Han population: a case-control study. BMC Med Genet 2009; 10: 71.
Levine SJ, Wenzel SE. Narrative Review: The Role of Th2 Immune Pathway Modulation in the Treatment of Severe Asthma and Its Phenotypes. Ann Intern Med. 2010;152:232–237. doi: 10.7326/0003-4819-152-4-201002160-00008
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Published: Ann Intern Med. 2010;152(4):232-237.
Asthma, Prevention/Screening, Pulmonary/Critical Care.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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