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Sep 12, 2013
 |  BC Innovations  |  Cover Story

TLR4 signaling in allergic asthma

Baylor College of Medicine researchers have uncovered a pathway in allergic asthma that opens up the potential for developing therapeutics that target the causes of the disease rather than just its symptoms.1 The team now has to show that the pathway, which involves degradation of the blood clotting protein fibrinogen by fungal allergens to cleavage products that activate toll-like receptor 4, also applies to other allergens.

Allergic asthma involves a magnified immune response to airway allergens that results in airway hyperresponsiveness, inflammation and constriction. Standard of care includes corticosteroids for general immune suppression and a combination of short- and long-acting bronchodilators to relax the airway smooth muscles and decrease constriction.

All standard-of-care drugs treat symptoms resulting from the inflammatory reaction rather than the source of the disease. Moreover, corticosteroids can cause increased susceptibility to infection, and bronchodilators can induce increased heart rates and hyperactivity.

Targeting the underlying causes of asthma has been hampered by an incomplete understanding of the mechanisms linking allergen exposure to the inflammatory reaction in the lungs.

Previous work by David Corry and Farrah Kheradmand at Baylor and by groups elsewhere has shown that proteinases from common allergens induce an adaptive immune response involving proinflammatory T helper type 2 (Th2) cell activation and production of proinflammatory cytokines.2

Corry is director of the Biology of Inflammation Center, chair in immunology, chief of immunology, allergy and rheumatology and a professor of medicine and of pathology and immunology at Baylor. Kheradmand is professor of medicine and immunology at Baylor.

One strategy to prevent Th2 cell activation is to agonize certain toll-like receptors (TLRs) including TLR7 and TLR9. Activating these receptors on dendritic cells polarizes naïve helper T cells to the Th1 subtype, thus decreasing the Th2 subtype that contributes to asthma.

There are at least six TLR7 or TLR9 agonists in clinical and preclinical development to treat asthma (see "TLR9 and TLR7 agonists in development for asthma").

Previous studies have found that another TLR, TLR4, may also play a role in asthma,3 although the mechanism underlying TLR4 activation in the disease has remained elusive.

Now, Corry, Kheradmand and colleagues have established a mechanistic link for the allergen-triggered activation of TLR4 and identified new therapeutic targets within the pathway to treat allergic asthma.

In mice, knockout of Tlr4...

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