Efficacy of Tremacamra, a Soluble Intercellular Adhesion Molecule 1, for Experimental Rhinovirus Infection

Turner, Ronald B.; Wecker, Margaret T.; Pohl, Gerhardt; Witek, Theodore J.; McNally, Eugene J.; George, Roger St.; Winther, Birgit; Hayden, Frederick G.

doi:10.1001/jama.281.19.1797

Cited by 190 publications

(140 citation statements)

References 32 publications

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…Indeed, a recombinant form of sICAM-1 has been shown to have inhibitory effects on HRV infection in vitro (17). Studies in chimpanzees (18) and humans (19) have shown recombinant sICAM-1 to have some prophylatic effects with reduced severity of experimental rhinoviral colds. A recent in vivo study investigated mICAM-1 expression on nasal scrape biopsies and sICAM-1 levels in nasal lavage fluid from separate volunteer groups inoculated with experimental rhinovirus (28).…”

Section: Discussionmentioning

confidence: 99%

Human Rhinovirus Selectively Modulates Membranous and Soluble Forms of Its Intercellular Adhesion Molecule–1 (ICAM-1) Receptor to Promote Epithelial Cell Infectivity

Whiteman

Bianco

Knight

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Human rhinoviruses are responsible for many upper respiratory tract infections. 90% of rhinoviruses utilize intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, which also plays a critical role in recruitment of immune effector cells. Two forms of this receptor exist; membrane-bound (mICAM-1) and soluble ICAM-1 (sICAM-1). The soluble receptor may be produced independently from the membrane-bound form or it may be the product of proteolytic cleavage of mICAM-1. The ratio of airway epithelial cell expression of mICAM-1 to the sICAM-1 form may influence cell infectivity and outcome of rhinovirus infection. We therefore investigated the effect of rhinovirus on expression of both ICAM-1 receptors in normal human bronchial epithelial cells. We observed separate distinct messenger RNA transcripts coding for mICAM-1 and sICAM-1 in these cells, which were modulated by virus. Rhinovirus induced mICAM-1 expression on epithelial cells while simultaneously down-regulating sICAM-1 release, with consequent increase in target cell infectivity. The role of protein tyrosine kinases was investigated as a potential mechanistic pathway. Rhinovirus infection induced rapid phosphorylation of intracellular tyrosine kinase, which may be critical in up-regulation of mICAM-1. Elucidation of the underlying molecular mechanisms involved in differential modulation of both ICAM-1 receptors may lead to novel therapeutic strategies. Human rhinoviruses (HRV)1 are the most frequent cause of upper respiratory tract infections known as the "common cold." Although these infections are generally mild and self-limiting, they inflict a heavy economical burden due to high loss of productivity and medical costs (1). Currently, there is no effective treatment for HRV infections; over the counter cold remedies only alleviate the symptoms but do not eradicate the virus.Primarily, HRV target epithelial cells for attachment and entry. These cells express intercellular adhesion molecule 1 (ICAM-1), the receptor for 90% of HRV serotypes (2). Both this major group of HRV and the 10% of HRV that use alternative receptors for cell attachment enhance cell surface ICAM-1 expression (3). This glycoprotein, belonging to the immunoglobulin supergene family, consists of five Ig-like domains (4); domains 1 and 2 have been shown to fit snugly in a key-lock relationship into reciprocal canyons on the HRV shell (5). In addition, to this critical role as a docking molecule during HRV infection, ICAM-1 through separate domains with its cognate ligand LFA-1 (CD18/CD11a) drives the migration of immuneeffector cells to sites of inflammation (6). While most studies refer to the membranous form of ICAM-1, a soluble form (sICAM-1) has also been described (7). The molecular mass of sICAM-1 is similar to the molecular mass of the extracellular domain of ICAM-1 (80 -114 kDa) depending on the level of glycosylation, suggesting that this soluble circulating form of ICAM-1 consists of most of the extracellular domain of membranous ICAM-1 (7). Several circulating isoform...

show abstract

Section: Discussionmentioning

confidence: 99%

Human Rhinovirus Selectively Modulates Membranous and Soluble Forms of Its Intercellular Adhesion Molecule–1 (ICAM-1) Receptor to Promote Epithelial Cell Infectivity

Whiteman

Bianco

Knight

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…90% of rhinovirus serotypes gain entry into epithelial cells using ICAM-1 cellular receptors and blockade of these receptors in experimental studies have shown reduced infection severity (Turner, Wecker et al 1999), but further study is required before this treatment option becomes widely available. Macrolide antibiotics, Bafilomycin A1 and Erythromycin have been shown to inhibit ICAM-1 epithelial expression and hypothesis about their potential as anti-inflammatory agents have yet to be definitive, as clinical proof is either negative or inconclusive (Suzuki, Yamaya et al 2002).…”

Section: Prevention and Treatment For Respiratory Virusesmentioning

confidence: 99%

“…Recently, an anti-rhinoviral agent known as Plecoranil, which acts by inhibiting the uncoating of Picornaviruses (Ledford, Patel et al 2004), the RV 3C protease inhibitor, Ruprintrivir (Hayden, Turner et al 2003) and soluble ICAM-1, Tremacamra (Turner, Wecker et al 1999) have shown promising results in early-stage clinical trials, but each of these medications was derailed by a combination of cost, pharmacokinetics, toxicity, drug interactions, and limited efficacy (Turner 2005).…”

Section: Prevention and Treatment For Respiratory Virusesmentioning

confidence: 99%

Viral Respiratory Tract Infections in Cystic Fibrosis

Wat¹

2012

Cystic Fibrosis - Renewed Hopes Through Research

View full text Add to dashboard Cite

“…Because 90% of HRV serotypes use the intercellular ahesion molecule 1 (ICAM-1) receptor for attachment to cells, preventing binding to this receptor has been explored therapeutically (119). Tremacamra, a soluble ICAM-1, was studied in a series of double-blinded studies where the agent was administered as a nasal spray solution or inhaled powder (120). It reduced the severity of experimental colds when administered less than 12 hours after HRV challenge.…”

Section: Pathogen-specific Therapymentioning

confidence: 99%

Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Martínez

2007

Proceedings of the American Thoracic Society

View full text Add to dashboard Cite

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the natural history of this chronic lung disorder. These events can be caused by a large number of infectious and noninfectious agents and are associated with an increased local and systemic inflammatory response. Their frequency and severity have been linked to progressive deterioration in lung function and health status. Infectious pathogens ranging from viral to atypical and typical bacteria have been implicated in the majority of episodes. Most therapeutic regimens to date have emphasized broad, nonspecific approaches to bronchoconstriction and pulmonary inflammation. Increasingly, therapy that targets specific etiologic pathogens has been advocated. These include clinical and laboratory-based methods to identify bacterial infections. Further additional investigation has suggested specific pathogens within this broad class. As specific antiviral therapies become available, better diagnostic approaches to identify specific pathogens will be required. Furthermore, prophylactic therapy for at-risk individuals during high-risk times may become a standard therapeutic approach. As such, the future will likely include aggressive diagnostic algorithms based on the combination of clinical syndromes and rapid laboratory modalities to identify specific causative bacteria or viruses.

show abstract

Efficacy of Tremacamra, a Soluble Intercellular Adhesion Molecule 1, for Experimental Rhinovirus Infection

Abstract: Tremacamra reduced the severity of experimental rhinovirus colds. Whether tremacamra will be useful clinically will require further study.

Cited by 190 publications

References 32 publications

Human Rhinovirus Selectively Modulates Membranous and Soluble Forms of Its Intercellular Adhesion Molecule–1 (ICAM-1) Receptor to Promote Epithelial Cell Infectivity

Human Rhinovirus Selectively Modulates Membranous and Soluble Forms of Its Intercellular Adhesion Molecule–1 (ICAM-1) Receptor to Promote Epithelial Cell Infectivity

Viral Respiratory Tract Infections in Cystic Fibrosis

Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Contact Info

Product

Resources

About