Recent Advances In Basic And Clinical Aspects In Inflammatory Bowel Diseases, As Crohn'S Disease And Ulcerative Colitis: Role Of Gastrointestinal Granulocytes

Rather than IBD being caused by excessive inflammation, the primary mechanism is actually that of an immunodeficiency. In this sense, there are four steps in the interaction between intestinal microbes and mucosal inflammation in individuals genetically predisposed to IBD. The first step is an interaction between intestinal microbes or their components and intestinal epithelial cells via receptors including TLRs, the second step an interaction between macrophages, DCs and mucosal lymphocytes, the third step an interaction between lymphocytes and vascular endothelial cells, and the fourth step an interaction between lymphocytes and granulocytes producing proinflammatory cytokines or free radicals and mucosal damage and repair. Recent therapeutic approaches for IBD are to block these four steps in the intestinal inflammation of patients.The majority of granulomas in CD may be formed within or near the walls of blood and lymphatic vessels, suggesting granulomatous vasculitis as an early element in the pathogenesis of this disease. Therefore, granulocytes are clearly implicated in the pathogenesis of IBD. Immunohistopathological studies have revealed accumulation and activation of granulocytes in actively inflamed intestinal mucosa of CD and UC patients. Animal studies have also revealed that abrogation of chemokines promoting granulocyte chemotaxis and circulation results in decreased severity of murine experimental colitis and that deletion of granulocytes by administration of antibody against neutrophils decreased severity of colonic inflammation and production of reactive oxygen species, suggesting a clear proinflammatory role of granulocytes in IBD.Furthermore, selective deletion of certain granulocyte-specific granule products results in attenuation of experimental intestinal inflammation. In this sense, studies demonstrate that intestinal mononuclear phagocytes can serve a protective role during development of acute colitis and that protection is associated with macrophage/dendritic cells-mediated down-regulation of neutrophil infiltration.Indeed, the development of biological agents such as infliximab to intercept TNF-alpha validates the current perception that cytokines and chemokines are major factors in the immunopathogenesis of IBD. Furthermore, major sources of inflammatory cytokines and chemokines include activated peripheral granulocytes and monocytes, which in patients with IBD are elevated with increased survival time and are found in vast numbers within the inflamed intestinal mucosa. Hence, elevated granulocyte and monocytes should be appropriate targets of therapy in IBD. Accordingly, in recent years technologies such as the Adacolumn have been developed for selective depletion of elevated granulocytes and monocytes/macrophages by extracorporeal adsorption and this have been associated with clinical efficacy in patients with active IBD.In conclusion, granulocytes are clearly implicated in the pathogenesis of IBD and, in the future, a better differentiation of leukocyte immunotherapies is clearly needed. Thus, prediction of therapeutic response to different biological agents or conventional drugs, and identification of different subgroups of IBD patients which may benefit from different biological agents, represent the challenges for the future.