Anti-selectin therapy for the treatment of inflammatory diseases.

ABSTRACT

Leukocyte migration into the tissues represents a key process in the pathogenesis of inflammatory diseases. Data obtained in clinical trials have convincingly shown that inhibition of leukocyte migration into the target organs represents an effective therapeutic approach for diseases in which inflammation has a noxious effect. Leukocyte tethering and rolling are the earliest steps of leukocyte adhesion cascade in inflamed vessels. Selectins are type I transmembrane glycoproteins that bind sialylated carbohydrate structures in a calcium-dependent manner and are involved in the tethering and rolling of leukocytes under physiological and pathological conditions. Three selectins have been identified L-, P- and E-selectin. Current understanding of the glycosylation-dependent selectin function reveals a complex role for selectins and their ligands during inflammatory diseases. Among selectin ligands, mucin P-selectin glycoprotein ligand-1 (PSGL-1) binds all three selectins and has a well-documented role in organ targeting during inflammation in animal models. However, although inhibition of selectins and their ligands in animal models of inflammatory diseases has proven the validity of this approach in vivo, only a limited number of anti-selectin drugs have been tested in humans. Recent results obtained in clinical trials for asthma and psoriasis show that, although very challenging, the development of selectin antagonists holds concrete promise for the therapy of inflammatory diseases.