Inflammatory bowel disease: Cytokines and cytokine therapies

Oral presentation

Recent data from various groups suggest that the activation of mucosal T lymphocytes by bacterial antigens plays a key role in the pathogenesis of inflammatory bowel diseases (IBD). Furthermore, adhesion molecules are thought to specifically recruit T lymphocytes to the inflamed bowel. T lymphocytes and their cytokines in turn play an important role in regulating mucosal immune responses in IBD patients as well as in animal models of chronic intestinal inflammation. In particular, an essential role for CD4+ T lymphocytes has been shown in many animal models of experimental colitis. Both Th1 and Th2 T cell subsets have been shown to induce chronic intestinal inflammation and the action of these T effector cells can be suppressed by cytokines produced by CD25+ Treg and Th3 cells such as IL-10 and TGF-beta. Furthermore, CD4+ T cells seem to play a key pathogenic role in the pathogenesis of human IBD. In addition, antibodies to TNF that are successfully used in treating Crohn´s disease patients have been shown to induce rapid mucosal T cell apoptosis (programmed cell death) within 2 days indicating that the therapeutic efficacy of these antibodies could be due to the elimination of T effector cells in the gut.

A possible explanation for increased T cell stimulation and activation in IBD is that T cells are continuously activated by bacterial antigens. In fact, studies by several groups suggested that IBD T cells are reactive towards the autologous intestinal flora. This concept is consistent with a study showing the development of early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. The hypothesis that intestinal T cell responses in IBD are driven by bacterial antigens is also supported by studies showing that intestinal inflammation in various T cell-dependent animal models of IBD is suppressed when mice are kept under germfree conditions and that monocontamination with certain bacterial strains can cause disease development. Furthermore, in some animal models colitis can by adoptively transfered by antigen-specific T cells that react with bacterial, luminal antigens.

Another aspect of interest for IBD pathogenesis is the existence of T cell resistance against programmed cell death in these diseases. In the normal gut, expansion of antigen-specific T cells may be important for host defense. On the other hand, this may lead to effector cell populations with substantial autoreactivity and the capacity to cause mucosal inflammation. To deal with this latter possibility, the mucosal immune system has evolved several strategies for the control of mucosal immune responses such as the regulation of programmed cell death or apoptosis, either that occurring via an active mechanism following TCR stimulation (activation-induced cell death) or that occurring via a passive mechanism following lymphokine (e.g., IL-2) withdrawal.

Interestingly, IBD T cells manifest increased resistance against apoptosis and ,in fact, T cell resistance against apoptosis appears to be a key factor for inappropriate T cell accumulation and the perpetuation of chronic mucosal inflammation in inflammatory bowel diseases (IBD). Finally, novel treatment modalities such as anti-TNF, anti-IL-12 and anti-IL-6R antibodies appear to suppress colitis activity by the induction of T cell apoptosis. These findings have important implications the design of more effective treatment regimens in IBD and suggest that selective T cell targeting might be very helpful for IBD therapy.

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