VCAM-1/alpha 4-integrin adhesion pathway: therapeutic target for allergic inflammatory disorders

Lymphocyte recirculation and leukocyte extravasation involve a multistep process that is central to immune surveillance and the rapid response of white blood cells to sites of injury or infection. Interaction of vascular adhesion molecules (VCAM-1, ICAM-1, and selectins) with ligands on the leukocyte surface (integrins, carbohydrates, and mucin-like molecules) regulate diapedesis. The nature of an inflammatory stimulus ultimately determines the pattern of endothelial adhesion molecule expression and the avidity state of their counterreceptors, thus dictating to a large extent whether a subclass of leukocytes will play a dominant role in the immune response. Immunoglobulin superfamily member VCAM-1 recognizes alpha 4 beta 1 integrin, expressed on all leukocytes except neutrophils. Blockade or inhibition of VCAM-1/alpha 4 beta 1 interaction is expected to have therapeutic potential in treating various inflammatory disorders and autoimmune diseases since this adhesion pathway has a major influence on eosinophil, lymphocyte, and monocyte trafficking. This review summarizes some of the strategies that are currently used to selectively inhibit the VCAM-1/alpha 4 integrin pathway, including soluble VCAM-Ig fusion protein, peptide antagonists, antisense oligonucleotides, natural products, and neutralizing antibodies to VCAM-1 or alpha 4 integrin.