Experimental immunomodulatory therapy of inflammatory bowel disease

S Schreiber
Netherlands Journal of Medicine 1998, 53 (6): S24-31
Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) of unknown etiology but demonstrate a rising incidence in many western countries. Although little is known about inflammatory pathomechanisms which are specific to either Crohn's disease or ulcerative colitis, a distinction between both diseases can often be made by typical clinical manifestations, endoscopic appearance or histologic characteristics. The immunology if mucosal inflammation in both diseases is characterized by an overwhelming preponderance of pro-inflammatory cytokine expression with an apparent inability to adequately downregulate immune activation. Moreover, it appears that Crohn's disease does not describe a single clinical entity: The ability to develop certain disease characteristics (e.g. fistula or stenosis formation, respectively) varies between individuals and may be a constant characteristic not being altered in the natural course of disease. From clinical observations it can be therefore concluded that disease subgroups may exist which could be distinctly different in disease pathophysiology and treatment response. With the development of defined immune interventions single steps in the immune cascade can be targeted and evaluated for therapy. Humanized monoclonal antibodies have been engineered which bind with a high affinity to tumor necrosis factor-alpha, a pro-inflammatory cytokine with particular importance in the immunoregulation of inflammation. Although the precise mechanism of action is not completely understood, it appears that a single infusion of this monoclonal antibody (cA2) can induce remission in a high percentage of steroid dependent, chronic active patients with Crohn's disease. The parenteral administration of interleukin-10 (IL-10), a contra-inflammatory cytokine, which downregulates immune activation in most immune and non-immune cells, also induces improvement in this patient group. At present it is still unclear, how interleukin-10 needs to be administered: Studies using intravenous application of IL-10 lead to very promising results, whereas the subcutaneous administration induced a considerable less impressive therapeutic effect. New therapeutic principles are appearing on the horizon, which have not been evaluated in a critical number of patients yet but appear promising because of the concept. One strategy will be the use of anti-sense oligonucleotides. Anti-sense oligonucleotides in the appropriate chemical structure can penetrate cells and neutralize a complementary sense-mRNA of the target molecule. Therefore, targeted molecules can be specifically eliminated in their expression directly on the transcriptional level. Interesting therapeutic trials are expected against adhesion molecules (ICAM-1) and pro-inflammatory signaling molecules (i.e. nuclear factor kappa B). The future development of immune therapies in IBD therefore holds great promises for better treatment modalities of inflammatory bowel disease but will also open important new insights into a further understanding of inflammation pathophysiology.

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