Subproject A7

By continuation of the investigation of gnotobiotic, mono-associated, and conventional mice differing in their expression of TLRs, nod proteins, or LBP, the role of the innate immune system in the pathogenesis of IBD shall be investigated in order to develop novel therapeutic intervention strategies focusing on TLR antagonists. By design, breeding and controlled colonization of genetically variant gnotobiotic mice in the first funding period the influence of genetic heterogeneity of the TLR system on the commensal flora and its relevance for the pathogenesis of IBD has been investigated. Here it was found that during ileitis a massive shift in flora towards Enterobacteriaceae occurs, which by stimulating the innate immune system via the LPS-TLR4-MyD88-axis is central for disease pathogenesis. Furthermore it was found that LBP, synthesized i.e. by gut epithelial cells, is of great importance for colitis development as LBP^-/- mice developed a much weaker experimental colitis as compared to control animals. In the next funding period the role of single strains of Enterobacteriaceae shall be confirmed by monocolonization of gnotobiotic mice, and the disease shall be positively influenced by TLR antagonists. In this funding period maturation of dendritic cells (DCs) and the role of T-cell subpopulations shall also be investigated. Finally LBP, which is a crucial immunomodulator of LPS-induced responses, shall be studied regarding its role in the pathogenesis of ileitis and colitis, and regarding its therapeutic potential by utilization of the LBP^-/- mouse, and by recombinant expression and application of naturally occurring LBP mutants.