Anti-Tnf Treatment Of Crohn'S Disease

Crohn's disease is characterized by transmural intestinal inflammation, most likely as a result of abnormal T-cell activation. Human studies indicate that T-cell activation occurs within the CD4+ compartment, and that activation of specific T-cell subsets may be confined to the intestinal mucosa. Recent studies in experimental animals have indicated that in normal mice mucosa inflammation is controlled by regulatory T-cells (within the CD4+/CD45Rb(low) compartment), and that normal CD4+/CD45Rb(high) T-cells can mediate extensive bowel inflammation in the absence of such regulatory cells. It should be noted that although CD45Rb(high)-dependent inflammation is antigen-driven (and does not occur in germ-free animals), no specific pathogen has been implicated. Normal homeostasis (i.e. the absence of inflammation) in the bowel mucosa is further dependent on the ability to secrete certain (anti-inflammatory) cytokines, including interleukin-10. Antigen-dependent T-cell activation may cause tolerance, apoptosis, or differentiation and proliferation. It is now well recognised that T-cell differentiation may result in the generation of two phenotypically-characterized subsets, called Th1 (producing mainly IL-IO and IL-4) and Th2 (producing interferon-gamma and TNF), and that such differentiation is under control of interleukin-12 (Th1) and interleukin 4/10 (Th2). The pathophysiological features of Crohn's disease strongly suggest this condition to be a consequence of uncontrolled Th1-differentiation. We have recently tested this hypothesis by treating patients with Crohn's disease using either a TNF-blocking antibody (thus inhibiting a Th1 response) or interleukin-10 administration (thus boosting Th2 responses). Both intervention modalities show promising results and may induce clinical and endoscopical remission in steroid-refractory patients. These data support the concept that Crohn's disease is a result of abnormally-polarised T-cell differentiation and confirm the feasibility of immune intervention in this disease.