ABSTRACT
KEY WORDS: IBD, Crohn’s disease, immunotherapy, T cells, cytokines, TNF
The past decades have dramatically increased our understanding of the pathophysiology of chronic inammatory bowel disease (IBD). This has mainly been facilitated by the advent of molecular biologic and recombinant techniques. The focus on immunological aspects, in particular on T-cell immunology with the analysis of regulatory cytokine signaling pathways has provided the basis for innovative treatment strategies. Many of these novel strategies are still experimental and subject to clinical studies, while others have already been incorporated into the treatment armamentarium of routine clinical management in IBD. The availability of an increasing number
Abstract .................................................................................................................. 105 Inammatory Bowel Disease ................................................................................. 106 Pathophysiological Role of T Cells ....................................................................... 106 Tumor Necrosis Factor-α ................................................................................................108 TNF Receptors and Signaling ................................................................................ 108
Iniximab .......................................................................................................... 112 Adalimumab ...................................................................................................... 113 Certolizumab ..................................................................................................... 114 CDP571 ............................................................................................................. 114 Etanercept .......................................................................................................... 114 Onercept ............................................................................................................ 115
Mechanisms of Action ........................................................................................... 115 Other Anti-TNF Strategies ..................................................................................... 116 Other Cytokine-Based and Anti-CD4+ T-Cell Approaches .................................... 116 Conclusions ............................................................................................................ 120 References .............................................................................................................. 120
of recombinant proteins in the treatment of IBD is a unique example for translational research from the bedside to the bench and back to the bedside. Interestingly, while the elucidation of the immunoregulatory pathomechanisms provided the basis for the development of these novel strategies, ongoing studies on the mechanisms of action of these substances in the clinical setting further increase our pathophysiological understanding considerably. This will further promote the development of more effective and more specic treatment strategies. It is the purpose of this chapter to outline our current pathoimmunological understanding of inammatory bowel disease with special focus on the characterization of those proinammatory players which have become targets for the rational development of recombinant antagonistic proteins. In particular, in trying to understand the mechanisms of action of the various different anti-TNF-strategies, important insights in TNF signaling pathways in inammatory bowel disease and other diseases have been made.
