Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: a randomized controlled study
| Autor: | Christian Herzmann, Ronald B. Turner, Mathew J. Loza, Robert Gordon, René Lutter, Sebastian L. Johnston, David Proud, Frédéric Baribaud, Brian Lipworth, Dave Singh, Alfred M. Del Vecchio, Philip E. Silkoff, Elliot S. Barnathan, Andreas Eich, Peter J. Sterk, Zuzana Diamant, Tjeert T. Mensinga, Patrick Branigan, Vibeke Backer, Scott A. Halperin, James E. Gern, Susan Flavin, Lani San Mateo |
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| Přispěvatelé: | Medical Research Council (MRC), National Institute for Health Research |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Allergy Adolescent Rhinovirus Immunology Anti-Inflammatory Agents medicine.disease_cause Placebo Gastroenterology Severity of Illness Index law.invention 03 medical and health sciences Young Adult 0302 clinical medicine Randomized controlled trial Double-Blind Method law Internal medicine medicine Immunology and Allergy Humans Adverse effect Asthma Aged Intention-to-treat analysis Picornaviridae Infections business.industry Area under the curve Antibodies Monoclonal Middle Aged medicine.disease Healthy Volunteers 030104 developmental biology Treatment Outcome Toll-like receptor 3 inflammation 1107 Immunology Anesthesia Disease Progression Female viral infection business 030215 immunology |
| Popis: | Background Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. Objective We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. Methods In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV 1 during 10 days after inoculation. Results In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV 1 decrease (least squares mean: CNTO3157 [n = 30] = −7.08% [SE, 8.15%]; placebo [n = 25] = −5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper ( P = .03) and lower ( P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. Conclusion In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need. |
| Databáze: | OpenAIRE |
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