The role of the histamine H4-receptor in DSS-induced colitis

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Inflammatory bowel diseases (IBD) represent a growing medical and health economical challenge, with the number of patients constantly rising over the past decades. In addition to the inflammatory symptoms, IBD patients have a higher risk to develop tumors and psychiatric disorders. Yet, treatment of IBD consists of treating the inflammatory symptoms only, and although in many cases expensive drugs are administered, merely in about half of the patients symptoms are ameliorated. Consequently, there is an urgent need for new treatment options. Starting point for the project applied for are studies that showed increased concentrations of histamine, a pro-inflammatory mediator, and an increased activity of mast cells, the main producers of histamine, in the colon of IBD patients. It can, thus, be concluded that blocking the histamine effects will probably improve the inflammatory symptoms in IBD patients. Interfering at the histamine effect by blocking specific receptors is the mechanism of action of already well-established drugs used to successfully treat other diseases (allergies, acid-related gastrointestinal disorders). However, these drugs, which are specific for the histamine H1-receptor (H1R) and the H2R, have been found to be ineffective in the therapy of IBD. The receptor which is most probably involved in inflammatory diseases is the H4R. In the planed project we, thus, test the hypothesis that the H4R is involved in the acute dextransulphate sodium (DSS)-induced colitis, a mouse model for IBD, and can be used as effective therapeutic target. In support to this hypothesis we have already shown in preliminary studies that in this model the absence of the H4R leads to a substantial amelioration of the disease.In the project, the cellular mechanisms underlying the function of the H4R in DSS-induced colitis-model shall be studied. The first specific aim is to thoroughly study the impact of the H4R on clinical and immunological parameters of the acute colitis. The second aim is to elucidate the question whether the functional expression of the H4R on eosinophilic granulocytes and/or mast cells plays a role in colitis. The third aim is to study whether the H4R expressed on hematopoietic or on non-hematopoietic cells is crucial for colitis. These studies constitute the basis for the development of potential new drugs to treat IBD.