Pharmiweb ChannelsAll | PharmaCo | Clinical Research | R&D/BioTech | Sales/Mktg | Healthcare | Recruitment | Pharmacy | Medical Comms

Pharmiweb.com RSS Feed Pharmiweb.com RSS Feeds

Advertising

Feature

OX40:OX40L interaction – evolving from a key component of autoimmunity to a possible target for cardiovascular disease

Posted on: 31 Jan 06

Summary

OX40 (CD134) is one of the newer tumor necrosis factor receptor (TNFR) family members. Expressed on CD4+ T-cells, its activation by OX40L, a type II membrane protein expressed on activated B-cells, dendritic cells and macrophages, plays an important T-cell co-stimulatory role. Today we highlight additional involvement in heart disease

DailyUpdates Jan 31st: OX40:OX40L interaction – evolving from a key component of autoimmunity to a possible target for cardiovascular disease

 

OX40 (CD134) is one of the newer tumor necrosis factor receptor (TNFR) family members.  Expressed on CD4+ T-cells, its activation by OX40L, a type II membrane protein expressed on activated B-cells, dendritic cells and macrophages, plays an important T-cell co-stimulatory role.

 

In our recent feature on Autoimmune Disorders & Transplant Rejection we describe the proof of concept for interrupting OX-40 activation as a candidate treatment for a number of autoimmune diseases.  For example, blocking OX40/OX40L interactions prevents islet destruction and insulitis in a model of diabetes. There is also data to support the concept of inhibiting this interaction for the treatment of rheumatoid arthritis and IBD.  With respect to the later neutralizing OX40L using OX40-Ig or anti-OX40L monoclonal antibody has produced quite remarkable results, blocking the development of experimental colitis

 

Dwarfing the autoimmune sector, cardiovascular disease has been the leading therapeutic category for over two decades and is set to continue its pace of expansion and dominance over the global drugs market. The cardiovascular market has expanded from a value of $60 billion in 1997 to $351.8 billion in 2003. With new drugs in the pipeline, competition in the cardiovascular market has never been greater (see The Cardiovascular Report). 

 

One area of the cardiovascular disease arena focuses on inflammation as an etiological factor in disease progression as well as a therapeutic target.  For example in Autoimmune Disorders & Transplant Rejection we discuss the prothrombotic effect of CD154 and also the atherogenic activity associated with CD40:CD154.   In today’s edition of DailyUpdates (Jan 31st, 2006) we highlight data suggesting that OX40:OX40L represents a further example of how a T-cell co-stimulatory molecule may contribute to heart disease.

 

A Nature Genetics paper published last year (37(4):365-72) reported on Ath1, a quantitative trait locus on mouse chromosome 1 that impacts on atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including the gene coding for OX40L. Mutating this gene was found to limit atherosclerotic lesions while its overexpression exacerbated atherosclerotic lesions.  Moreover, in two independent human populations, polymorphisms in the OX40L genotype increased the risk of myocardial infarction in humans.

 

In the BBRC paper highlighted today, the same group reported that a polymorphism in intron 5 of the OX40L gene was associated with precocious myocardial infarction.  This polymorphism was suggested to affect splicing.  OX40L is expressed by activated vascular endothelial cells at sites of inflammation and might as such play a role in extravasations of OX40 positive T-cells.  Given the role that immunocytes play in atherosclerosis, alterations in the OX40L:OX40 axis could quite feasibly modify the genesis of heart disease. Although the exact functional consequences of the polymorphism highlighted today requires further study, the therapeutic benefits of targeting OX40L:OX40 interaction may extend past autoimmune disease to encompass the massive area of cardiovascular disease.

LeadDiscovery

Last updated on: 27/08/2010 11:40:18

Advertising
Site Map | Privacy & Security | Cookies | Terms and Conditions

PharmiWeb.com is Europe's leading industry-sponsored portal for the Pharmaceutical sector, providing the latest jobs, news, features and events listings.
The information provided on PharmiWeb.com is designed to support, not replace, the relationship that exists between a patient/site visitor and his/her physician.