Conflict of interest: Selleckchem Everolimus A. V. S. H. and H. M. are named inventors on a composition of matter patent for MVA85A filed by the University of Oxford, and are shareholders in a Joint Venture formed for the

further development of this vaccine. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. “
“The development of clinical therapeutics that interfere with the migration of leukocytes has revolutionized the treatment of multiple sclerosis and holds great promise for the treatment of a wide range of inflammatory diseases. As the molecules essential for the multi-step adhesion cascade that mediates cellular migration have been elucidated, the number of potential targets available to modulate leukocyte trafficking

has increased exponentially. In this Viewpoint, we briefly review our current understanding of these mole-cular targets and how these targets vary by tissue and leukocyte subset with emphasis on T cells. We then describe the two currently approved therapeutics that target cell migration, natalizumab and fingolimod, and discuss how an improved understanding of their function could pave the way for the development of safer and more efficacious therapies for inflammatory and autoimmune diseases. Nearly 50 years ago, Gowans and Knight published a seminal study demonstrating that labeled lymphocytes injected into rats migrated C646 research buy from the blood into secondary lymphoid organs (SLOs) and then returned to the circulation via the thoracic duct [1]. In Levetiracetam an accompanying paper by Marchesi and Gowans, lymphocytes were observed to adhere to what are now called high endothelial venules and pass through the endothelial layer in a directed migration into the lymph node [2]. This process was hypothesized to be selective, as only small lymphocytes emigrated from the venules while larger lymphocytes were excluded. In the time since these first observations were made, knowledge of the molecular mechanisms

that underpin lymphocyte trafficking has exploded. The selective migration observed by Marchesi and Gowans is now understood to be a tightly orchestrated multistep adhesion cascade, regulated by selectins, integrins, chemokines, and chemoattractant lipids, that specifically directs the trafficking of leukocytes into sites essential for their function. Such an improved understanding of the underlying mechanisms involved has resulted in the identification of an array of potential drug targets aimed at modulating cell migration in order to treat a broad range of autoimmune and inflammatory diseases. Today, two drugs targeting cell migration are approved for clinical use in multiple sclerosis, one of which is also approved for Crohn’s disease; and many more are currently in clinical trial for these and other inflammatory diseases.