The role of immunosuppression and type II immune response in the course of acute and chronic pancreatitis.

• Applicant: Privatdozent Dr. Matthias Sendler
• Subject Area: Gastroenterology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 384909139

The severity of acute and chronic pancreatitis is largely determined by the immune response. This systemic immune response is responsible, on the one hand, for the complications associated with severe necrotizing pancreatitis and, on the other, for the progressive pancreatic fibrosis during chronic pancreatitis. In preliminary studies we could show that macrophages infiltrating the damaged organ play a decisive role in the regulation of this systemic immune response. Macrophages in the necrotic areas of the pancreas are activated via damage associated molecular patterns (DAMPs) and differentiate into an M1-like phenotype. Under these primarily sterile conditions, the cells release increased amounts of cytokines of the IL-1 family, such as IL-18, which leads to a shift in T-cell differentiation towards a suppressive Treg and fibrinogenic Th2 response. We observed a strong activation of the IL-10 receptor pathway as well as the Stat6 pathway. In this follow-up project, based on the previous results, the signalling pathways behind the regulatory/suppressive immune response and the type II response will be further characterised in order to develop therapeutic approaches. In models of acute and chronic pancreatitis the interactions of the suppressive Treg response, the macrophage response and the general type II immune response will be investigated. On the one hand, the influence of the suppressive cytokines IL-10 and IL-35 will be investigated in more detail and, on the other hand, the role of the transcription factor Stat6, which is essential for the Type II immune response, will also be studied. For this purpose IL10fl/fl mice will be crossed in CD4-Cre and LyzM-Cre transgenic mouse lines to study the effect of IL-10 in CD4+T cells as well as in cells of myeloid origin such as monocytes/macrophages and granulocytes against the background of pancreatitis. Ebi3-/- and IL27ra-/- will be used to investigate the influence of the Treg cytokine IL-35 and the cytokine IL-27. Furthermore, stat6-/- mice will be used to investigate the influence of the early and late type II immune response on the course of the disease. These experiments will clarify the extent to which the regulatory or suppressive immune response and the type II immune response are synergistic. On the one hand, the mechanisms behind Treg induced and macrophage induced immunosuppression will be elucidated. As well as the influence of the Stat6 signaling pathway. This will be done by comparing acute and chronic pancreatitis to identify a time window for optimal treatment.

• DFG Programme: Research Grants