Research Article: An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Date Published: August 1, 2013

Publisher: Public Library of Science

Author(s): Stephanie Traub, Alexandra Nikonova, Alan Carruthers, Rebecca Dunmore, Katherine A. Vousden, Leila Gogsadze, Weidong Hao, Qing Zhu, Katie Bernard, Jie Zhu, Michael Dymond, Gary R. McLean, Ross P. Walton, Nicholas Glanville, Alison Humbles, Musa Khaitov, Ted Wells, Roland Kolbeck, Andrew J. Leishman, Matthew A. Sleeman, Nathan W. Bartlett, Sebastian L. Johnston, Andrew Pekosz.

http://doi.org/10.1371/journal.ppat.1003520

Abstract

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo.

Partial Text

Human rhinoviruses (HRVs) infect the upper respiratory tracts of healthy subjects and cause around three quarters of common colds [1], [2]. Recently, it has become clear that HRVs are also major causes of severe, life-threatening illnesses in susceptible populations: 50–85% of acute asthma exacerbations are now known to be caused by HRV infections across all age groups [3], [4], [5], [6]. Further, wheezing illnesses in infancy caused by HRVs are strongly associated with a very high risk of later development of childhood asthma [7], [8], [9]. HRV infections are also associated with the majority of acute exacerbations of chronic obstructive pulmonary disease (COPD) [10], [11] and cystic fibrosis [12] and cause life-threatening illnesses in susceptible populations such as infants [13], the elderly [14] and immuno-compromised individuals [15]. Against this background, there is an urgent need to develop effective medications to combat HRV induced illnesses. To date there are no licensed treatments or vaccinations.

Human rhinovirus infection is the most common infection afflicting mankind and is responsible for enormous morbidity and societal costs as the major cause of the common cold. It also causes severe morbidity, mortality and health care costs as a key trigger of acute exacerbations of lung diseases such as asthma, COPD and cystic fibrosis. In this study, we demonstrate that an anti-ICAM-1 domain-specific antibody can effectively block entry and replication in an in vivo model of human rhinovirus infection and reduce rhinovirus-induced exacerbation of allergic airway inflammation, without preventing ICAM-1 interaction with its cellular ligand LFA-1, which is required for cell recruitment during respiratory infections. Thus 14C11 and other antibodies with similar specificities could be useful agents to help reduce rhinovirus induced respiratory exacerbations. .

 

Source:

http://doi.org/10.1371/journal.ppat.1003520

 

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