IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers

Abstract

Background: Asthma with neutrophil predominance is challenging to treat with corticosteroids. Novel treatment options for asthma include those that target innate immune activity. Recent literature has indicated a significant role for IL-1β in both acute and chronic neutrophilic asthma.

Objective: This study used inhaled endotoxin (LPS) challenge as a model of innate immune activation to (1) assess the safety of the IL-1 receptor antagonist anakinra in conjunction with inhaled LPS and (2) to test the hypothesis that IL-1 blockade will suppress the acute neutrophil response to challenge with inhaled LPS.

Methods: In a phase I clinical study 17 healthy volunteers completed a double-blind, placebo-controlled crossover study in which they received 2 daily subcutaneous doses of 1 mg/kg anakinra (maximum dose, 100 mg) or saline (placebo). One hour after the second treatment dose, subjects underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 4 hours after inhaled LPS. The effect of anakinra compared with placebo on airway neutrophil counts and airway proinflammatory cytokine levels after LPS challenge was compared by using a linear mixed-model approach.

Results: Anakinra pretreatment significantly diminished airway neutrophilia compared with placebo. LPS-induced IL-1β, IL-6, and IL-8 levels were significantly reduced during the anakinra treatment period compared with those seen after placebo. Subjects tolerated the anakinra treatment well without an increased frequency of infections attributable to anakinra treatment.

Conclusions: Anakinra effectively reduced airway neutrophilic inflammation and resulted in no serious adverse events in a model of inhaled LPS challenge. Anakinra is a potential therapeutic candidate for treatment of asthma with neutrophil predominance in diseased populations.

Keywords: Endotoxin; IL-1 receptor antagonist; IL-1β; LPS; anakinra; asthma; induced sputum; innate immunity; neutrophil.

Conflict of interest statement

The rest of the authors have declared that they have no conflicts of interest.

Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Phase I study design in healthy human volunteers

Randomized, placebo controlled crossover study of the interleukin-1 receptor antagonist, anakinra, and saline (placebo) in 17 healthy volunteers. Subjects were challenged with inhaled LPS (20,000 EU of CCRE), followed by sputum induction 4 hours after the LPS challenge.

Figure 2. Interleukin-1 receptor antagonist levels are increased in blood, but not sputum with anakinra treatment

Levels of interleukin-1 receptor antagonist were measured in sputum (A) and blood (B) at baseline visit, and 4 hours after inhaled LPS challenge with anakinra or placebo treatment. A linear mixed model approach was used to calculate the treatment effect comparing anakinra to placebo

Figure 3. Anakinra pretreatment reduces airway neutrophilia after LPS exposure

Percent neutrophils (A), neutrophils per mg sputum (B), percent macrophages (C), and macrophages per mg sputum were determined from induced sputum samples taken at baseline visit, and 4 hours after inhaled LPS challenge with anakinra or placebo treatment. Wilcoxon-signed rank tests were used to compare either post-LPS anakinra or placebo levels to baseline levels. A linear mixed model approach was used to calculate the treatment effect comparing anakinra to placebo

Figure 4. Anakinra pretreatment reduced the increase in sputum IL-1β, IL-6, and IL-8 after inhaled LPS challenge

Levels of IL-1β (A), TNF-α (B), IL-6(C), and IL-8 (D) were measured from induced sputum taken at baseline visit, and 4 hours after inhaled LPS challenge with anakinra or placebo treatment. Wilcoxon-signed rank tests were used to compare either post-LPS anakinra or placebo levels to baseline levels. A linear mixed model approach was used to calculate the treatment effect comparing anakinra to placebo.