Projekte der AG Siegmund "Chronische Darmentzündung"

Creeping fat represents a disease characterizing finding in Crohn’s disease but its impact on intestinal inflammation and epithelial barrier function is unknown. The present project aims to define how intestinal barrier defects shape the homeostasis of mesenteric fat, how these alterations confer to an alternative intestinal barrier and how creeping fat modulates epithelial resistance as well as intestinal immune cell composition and immunity. We are using colitis models, a fat-depleting mouse model including transplantation of adipose tissue and comprehensive immune phenotyping of the respective tissue to decipher the interplay between mesenteric fat, immune cells and the epithelial barrier.
These data will be subsequently correlated to results obtained from immune cell analyses of human tissues from our Crohn’s disease patient cohort.

Globally, colorectal cancer (CRC) is second leading cause of cancer death. CRC patients do not respond well to chemotherapy or immunotherapy due to low immunogenicity of many CRC tumors. Macrophages and MDSCs are one of major infiltrates in tumor microenvironment (TME). Various factors in the microenvironment mediate differentiation of myeloid precursors into MDSC or the immunosuppressive tumor associated macrophages (TAMs). TAMs suppress anti-tumor immune responses via regulatory T cell/NK cell activation or apoptosis, and also facilitate angiogenesis and metastasis. Since TAMs in cancer correlate positively with all stages of tumor progression, it is critical to target this cell type while treating cancer. We were the first, to describe the impact of lipid droplet formation on the suppressive capacity of TAMs and the first to attack this suppressive phenotype by inhibitors of enzymes for fatty acid metabolism. The main concept of our research is to support (re)activation of T cells that are suppressed via immune regulatory macrophages such as TAMs.

Histone deacetylase (HDAC) inhibitors are known to modulate the immune response and are currently tested in a great number of clinical trials as anti-cancer drugs. Recently, we could show that inhibiting HDACs does not only modulate T-cell responses but also protects the integrity of the epithelial barrier during inflammation and supports its regeneration. Therefore, targeting HDACs in epithelial cells as a treatment for inflammatory conditions of the gastrointestinal tract could represent a promising, new therapeutic approach. In order to determine the functions of single HDACs in epithelial cells, we use 3-dimensional and 2-dimensional culture systems of primary cells from mouse and human. These so-called organoids reflect cellular composition and cell-cell interactions in the gut much more accurately than conventional cell lines. Combining the organoid technology with conditional knockout and overexpression systems, we use a variety of different functional assays to investigate the importance of specific HDACs for organoid morphology, cell differentiation, stem cell signaling, proliferation, viability, barrier integrity, and gene expression.

In our most recent study, we were investigating whether tumor necrosis factor-α (TNF) production by peripheral blood mononuclear cells serves as a relevant predictor. A substantial rate of primary non-response to Infliximab (IFX) in patients with inflammatory bowel disease (IBD) emphasizes the need for predictive markers for treatment response. Responders had shorter disease duration, higher Limberg score and produced significantly more TNF and IL-6 at baseline compared to nonresponders. Being high-TNF-producer at baseline was independently associated with response to IFX in multivariate analysis. High TNF production of CD14+ cells at baseline predicts response to IFX in IBD.