Anakinra as a Rescue Treatment for Allergic Inflammation

Asthma is an increasingly common chronic illness with higher rates of hospitalization for exacerbation than many other chronic conditions. In 2009, total asthma costs in the U.S. were estimated at $56 billion per year, and over half the overall asthma-related costs were attributed to inpatient hospitalization. Allergen exposure and viral infection are among the most common triggers for asthma exacerbations. Exacerbations of allergic asthma are characterized by an early phase response, mediated by release of preformed mediators like histamine from mast cells, and a late phase response 3-7 hours later mediated by chemokines and cytokines, including IL-1beta (IL-1b), that attract leukocytes such as neutrophils and eosinophils to the airways, increase mucus production, trigger airway smooth muscle contraction, and result in airway constriction and airway hyper-reactivity.

While corticosteroids are considered a mainstay of treatment for asthma exacerbation regardless of the trigger, there are limitations to their effectiveness in the acute setting including the initial lag period of 4-6 hours or more before therapeutic effect and the concern for broad immune suppression. Corticosteroids are often ineffective in treating the neutrophilic component of airway inflammation seen with allergen-induced airway inflammation. Time to therapeutic benefit is key in preventing patient morbidity and mortality. Currently there is an urgent need for anti-inflammatory treatments that work quickly and effectively in acute asthma exacerbations.

The investigators propose that IL-1 blockade can achieve these ends and perhaps complement corticosteroid actions. Anakinra is an FDA-approved recombinant form of human IL-1 receptor antagonist (IL-1RA), a natural anti-inflammatory cytokine that competes with agonist binding to the IL-1 receptor, suppressing IL-1b and IL-1a signaling. Numerous murine and in vitro studies indicate that IL-1 signaling mediates key features of allergen-induced airway inflammation, including eosinophil recruitment and mucin production.

IL-1 receptor activity is important for eosinophil airway recruitment after allergen challenge through inducing endothelial cell adhesiveness and through increased mRNA expression of the eosinophil chemokine, eotaxin in pulmonary epithelial cells. IL-1 receptor type 1 (IL-1R1)-deficient mice demonstrate reduced allergic (eosinophilic) lung inflammation. Most pertinent to this project, anakinra treatment of wild type BALB/c mice prior to OVA challenge severely dampened airway eosinophil recruitment, cytokine responses, airway resistance and goblet cell numbers. In humans undergoing nasal allergen challenge, nasal secretions showed a biphasic pattern of IL-1b secretion that coincided with the early phase and late phase allergic responses. These data collectively suggest that IL-1 signaling is important in the allergic eosinophilic response and that anakinra has high potential to reduce eosinophilic inflammation.

Mucus accumulation is also a feature of allergen-induced inflammation and likely results from hypersecretion of mucus and failure of the mucociliary apparatus to effectively clear this mucus and airway debris. MUC5B and MUC5AC are the major secreted mucins in the human respiratory tract. IL-1b alone has been shown to induce increased epithelial cell mRNA expression of the mucin genes MUC5B and MUC5AC.

Anakinra is an ideal candidate to test as a rescue treatment for acute allergic inflammation due to its fast onset of action (reaching peak concentrations in 3-7 hours), and a short 4-6 hour half-life. Our objective is to determine if one treatment of anakinra mitigates a). eosinophil activation and recruitment and b) mucin secretion, after nasal allergen challenge, to ultimately assess if anakinra can mitigate key inflammatory features of asthma exacerbations. We expect that anakinra treatment will reduce nasal airway eosinophil recruitment, eosinophil activation, release of inflammatory mediators, mucins, and gene expression changes in epithelial cells after nasal allergen challenge based on pre-clinical data using anakinra with OVA challenge.