The CD40/CD40L costimulatory pathway in inflammatory bowel disease

Abstract

Many different types of immune and non-immune cells are involved in IBD pathogenesis, and they communicate with each other utilising a variety of stimulatory and costimulatory pathways. Among these, the CD40/ CD40L costimulatory pathway is of particular interest because of its diffuse distribution, potency, and variety of actions. Interactions between CD40 and CD40L expressing cells impact on multiple biological phenomena directly relevant to intestinal inflammation, including antibody production, activation of macrophages and dendritic cells, production of proinflammatory cytokines, chemokines, prostaglandins, proteolytic enzymes, and NO, and upregulation of adhesion molecules. There is objective evidence that the CD40/CD40L costimulatory pathway is activated in IBD tissue, as demonstrated by a marked increase in the number of cells expressing high levels of CD40 and CD40L, and the presence of elevated levels of sCD40L in the circulation of IBD patients. The contact of CD40L+ T cells and CD40L+ platelets with CD40+ mesenchymal and endothelial cells results in enhanced production of chemokines and expression of adhesion molecules that lead to the recruitment of more T cells which may become activated in the inflamed mucosa, express CD40L de novo, and induce further chemokine production, creating a vicious cycle of cell interactions that promote chronic intestinal inflammation. Based on presently available evidence, blockade of CD40/ CD40L interactions may provide therapeutic benefits to IBD patients. This is strongly supported by the clinical and histological improvement observed in various animal models of experimental colitis treated with CD40L antibodies. Monoclonal antibodies against CD40 and CD40L are available for use in humans with IBD and several other autoimmune and chronic inflammatory conditions. The results of ongoing and future clinical trials will define the value of blocking the CD40 pathway within the expanding armamentarium of biological therapies for IBD.