Projects of AG Siegmund "Intestinal Inflammation and Tumor Immunology"

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Collaborative Research Center "Immune-Epithelial Communication in Inflammatory Bowel Diseases" (TRR241)

Britta Siegmund and Christoph Becker from the Universitätsklinik Erlangen are the initiators and spokes persons of the TRR241.
The TRR241 started 2019 and is a joint research initiative of researchers in Erlangen, Berlin, Kiel and Innsbruck supported by the German Research Foundation (DFG). The TRR241 aims to better understand the molecular and cellular processes that lead to the development of Inflammatory Bowel Diseases (Crohn’s disease and ulcerative colitis), chronic relapsing inflammatory diseases of the gastrointestinal tract.

Mesenteric fat - an immunological barrier in Crohn's disease

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.

Impact of nutritional antigens on the systemic and mucosal immune system

One of the hallmarks of inflammatory bowel diseases is a dysregulation of the intestinal immune system. The immune system is linked to food antigens through the Peyer´s patches (PP) in the ileum having a major role in the induction of oral tolerance. Murine data indicate that food antigens induce an activation and subsequent apoptosis of the CD4+ T-cells in the PP thus maintaining the healthy balance of the mucosal immune system. The fate, phenotypic and functional analysis of human PP CD4+ T cells are analysed with flow cytometry, mass cytometry (CyTOF) and imaging mass cytometry (IMC). Next to the local analysis the systemic impact of nutritional antigens is analysed in this project. Food-antigen specific T cells with the antigen-reactive T cell enrichment (ARTE) method are quantified and further characterized in IBD and celiac disease patients. This project might give insights of the influence of food antigens on the immune system in IBD patients.

Fatty acid metabolism in tumor associated macrophages

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.

Multi-dimensional Immunophenotyping in IBD

Inflammatory bowel disease (IBD) is a group of complex autoimmune diseases that includes Ulcerative Colitis (UC) and Crohn´s disease (CD). Although IBD pathogenesis has been at the center of scientific interest for years, up to date the complex mechanisms underlying the disease are yet unrevealed. With the help of Mass Cytometry, we aim to elucidate how cytokine production and activation of several cell subtypes including B cells, T cells, neutrophils, monocytes and macrophages are modulated in UC and IBD patients. To do so, we perform deep immune-phenotype clustering analysis on human immune cells from peripheral blood, intestinal mucosa or intestinal fat tissue. Particularly, our lab is interested in investigating immune signature of IBD patients with rare phenotypes.

HDAC7 in intestinal epithelial cells

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.

Role of HDAC7 in CD8 effector and memory formation

Our research interest lies in delineating the biological role of HDAC7 in CD8+ T cells in the context of viral infection and tumor surveillance. By using HDAC7 conditional knockout mice, we demonstrated a critical role for this enzyme for survival and metabolic regulation in cytotoxic T cells. We are now investigating the underlying mechanisms by studying its transcriptional and epigenetic regulation as well as the respective protein interaction network.

Clinical research for diagnosis and therapy of IBD

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.