MIF in intestinal inflammation

Inflammatory bowel disease (IBD) is a common disorder with a prevalence of 80-200/100000 population. Like many other chronic inflammatory or autoimmune disorders, IBD seems to result from complex interactions among susceptibility genes, the environment, and the immune system. The current working hypothesis states that IBD is due to a dysregulated mucosal immune response, particularly a CD4 + T-cell response, to antigens of the enteric bacterial flora in a genetically susceptible host. This complex immune interactions are mainly directed via soluble mediators, including cytokines, chemokines and growth factors. This "cytokine" concept in IBD has been recently demonstrated to be of clinical importance as neutralization of one of those critical proinflammatory cytokines, namely TNFa, induces clinical remission in patients with Crohns disease. Recently it has been demonstrated that murine colitis is dependent on the continuous production of the proinflammatory cytokine macrophage migration inhibitory factor (MIF). This cytokine is of special interest, as it reflects one of the most potent proinflammatory cytokines and acts as a physiologic endogenous steroid antagonist. We want to further characterize its role in human IBD studying tissue expression, synthesis by lamina propria mononuclear cells (LPMNC) and dendritic cells (DC). In addition, we address Real-time PCR to measure mRNA tissue levels. MIF has been shown to be of central importance in the TNBS and CD45RB hi transfer model of murine colitis. In further studies, we want to evaluate the role of MIF in the oxazolone mouse model, which is regarded as a murine model of ulcerative colitis. In vivo neutralization studies should identify the pathophysiologic relevance of MIF in this model of intestinal inflammation. Experiments will include detailed studies with LPMNC and spleen T cells. Finally we will address the role of MIF in three knockout models, including IL-10 -/-, IL-16 -/- and pentraxin 3 -/- mice. IL-10 -/- mice develop spontaneous enterocolitis, which is not known so far for the other two knockout models. The proposed experiments should help to further characterize the role of MIF in human IBD and some forms of experimental colitis providing the basic concept for potential new therapies.

The research project P15783 was mainly focusing on the topic inflammation and gut/liver diseases. Funding of P15783 allowed to gain and develop critical new knowledge in the area of cytokine biology in gastrointestinal diseases and biology of antigen presenting cells (i.e. dendritic cells; DCs). Both mediators of the immune system (i.e. cytokines) as well as various cell types (i.e. DCs) are involved in the pathobiology of chronic inflammatory bowel diseases (IBD). Major aims of our research therefore have been clarification and identification of new interactions between cytokines and various cell types such as DCs. One of the major results from our research efforts was the finding that one of the most potent proinflammatory cytokines, namely interleukin-18 (IL-18), attracts plasmacytoid DCs and via other specific DCs (i.e. DC2) is able to control the immune response (i.e. Th-1 response). Those DC2 so far have been believed to support mainly the development of a more Th-2 response. This finding has been published in the well known and prestiguous Journal Blood. Clinical relevance of these in vitro findings then has been transformed to patient reality as we could demonstrate that IL-18 is also a potent and important cytokine in IBD (Ludwiczek O et al, Eur Cytok Netw 2005). We were also one of the first groups demonstrating the presence and localization of mature and immature DCs in IBD (Kaser A et al. J Clin Immunol 2004). In this remarkable work we could also identify the major cytokine/chemokine which attracts DCs into diseased tissue, namely CCL20. Another important research effort dealt with the issue osteoporosis and inflammation/IBD. Mediators of the immune system produced in the inflamed gut might contribute to osteoporosis which is highly prevalent also in very young patients with IBD. (Moschen A et al, Gut 2005). We were able to publish 16 additional Original Articles besides these four mentioned publications funded by this FWF project. With our research efforts we significantly contributed to a better understanding of the complex network of mediators of the immune system and various cell types in chronic inflammatory conditions. Such new knowledge is fundamental to develop better treatments for these miserable diseases in the future. Progress in the pathobiology of inflammatory pathways has been tremendous in the last years and definitely accompanied by the availability of better treatments such as the anti-tumor necrosis factor agents infliximab or etanercept.