IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers - 05/02/15
, Katherine Mills, BA a, Martha Almond, RRT a, Krista Todoric, MD a, Maria M. Aleman, PhD a, Hongtao Zhang, BS b, Haibo Zhou, PhD b, David B. Peden, MD, MS aAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Endotoxin, neutrophil, asthma, induced sputum, LPS, IL-1β, IL-1 receptor antagonist, anakinra, innate immunity
Abbreviations used : ANC, IDC, IL-1ra, RA, UNC, WBC
Plan
| M.L.H. is supported by National Institute of Environmental Health Sciences grant K23-ES021745. K.M., M.A., H.Z., H.Z., and D.B.P. are supported by National Institute of Allergy and Infectious Diseases grant U19AI077437. |
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| Disclosure of potential conflict of interest: This study was funded by a grant from the National Institute of Allergy and Infectious Diseases (U19AI077437). The authors declare that they have no other relevant conflicts of interest. |
Vol 135 - N° 2
P. 379-385 - février 2015 Retour au numéro
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