E1: The effect of CCR4 on immuno-competent cells in inflammation

Graduate student: Manja Appelt, Julia van der Linde
Tutor: Prof. Dr. Stefan Maier, Dr. Tobias Traeger
Chemokines and their receptors play a crucial role in migration and homing of different cell types and especially immune cells. It is known, that the chemokine-receptor 4 (CCR4) is located on cells which are involved in inflammation. Th2 lymphocytes and some regulatory T-cells express CCR4. MDC and TARC, the cognate ligands of CCR4, can be detected in lymphatic tissues and sites of inflammation. Previous results point to an essential role of CCR4 in systemic microbial infection (Sepsis). Sepsis is a life threatening disease with high mortality. The animal model CASP, which is established in our group, closely mimics the clinical course of sepsis following anastomosis insufficiency. By using CCR4 knock-out mice, the role of CCR4 in polymicrobial sepsis is analyzed in the present project. Actual and future experiments will focus on thrombocytes in the context of experimental sepsis. It is known, that CCR4 is expressed on the surface of thrombocytes. It becomes more and more evident, that thrombocytes are important immomodulating “cells”, however, their biological functions during systemic peritonitis are poorly understood. Therefore, we established an intensive collaboration with the group of Prof. Greinacher to analyze thrombocyte function during experimental peritonitis especially regarding CCR4.

E2: Identification of changes in immune-homeostasis resulting from tissue injury following major surgery or cerebral stroke

Graduate students: Antje Vogelgesang, Juliane Schulze, Vivien Henck, Rakesh Chandode, Huu Ngyuen Hung, Laura Klene
Tutor: Robert Jack, Alexander Dressel, Stefan Maier
Tissue injury has a profound impact on the immune homeostasis. This project aims to elucidate the complex mechanisms induced by non-infectious tissue damage which may in turn predispose to severe infection. The project consisits of three major parts: In the first we will use microarrays to define patterns of gene expression in T cells and monocytes during the period of immune dysregulation which follows stroke and trauma. In the second we will addresses the question of how circulating cells in the blood, in particular monocytes, can detect tissue damage within 2 h after trauma. In the third we will compare the gene expression patterns in immune cells from humans and animals after cerebral stroke and take advantage of genetically altered mice to elucidate the underlying molecular mechanisms.

E3: Murine models of inflammation-induced immune suppression

Graduate student: Katrin Kleinfeldt
Tutor: Barbara Bröker, Markus Lerch, Julia Mayerle
This project is based on the following hypothesis: A compensatory immune paralysis is a general consequence of systemic inflammation, whether this is caused by generalized infection or by sterile severe tissue damage. Initially, a murine model of acute pancreatitis will be used to characterize the cellular and molecular mechanisms of post-pancreatitic immune suppression. The mechanisms identified will then be compared with those operating in colon ascendens stent peritonitis (CASP) - a model of acute peritonitis.

E4: The role of pattern recognition receptors in pancreatitis

Graduate student: Ravi Malla Sudarshan, Annett Günther
Tutor: Ulrich Weiss, Markus Lerch
During an episode of acute pancreatitis about 5-10% of all patients develop bacterial infection with severe outcome. Recent studies on chronic inflammatory diseases such as inflammatory bowel disease imply that mutations of pattern recognition receptors (e.g. NOD2/CARD15, Toll-like receptors) may display potential risk factors for bacterial infection. Analysis of a genetic predisposition for bacterial infection will be studied. Therefore a collective of patients with severe pancreatitis will be screened for the presence of NOD2 polymorphisms R702W, G908R and 3020-InsC and the TLR4 polymorphisms D229G and T399I. In NOD2 and TLR4 knock-out animals the specific role of these receptor genes in disease severity and progression of acute pancreatitis will be investigated. Studying mechanisms in signal transduction and expression of specific cytokine profiles in primary pancreatic cell lines will give further indications on the role of pattern recognition receptors in pancreatitis.

E5: Role of IDO in immune paralysis

Graduate student: N.N.
Tutor:  Alexandra Westerholt
Recently we showed that stress induced tryptophan catabolism along the kynurenine pathway is responsible for immune suppression and depression-like behaviour in mice. Here, we want to identify the relationship between HPA axis activation and IDO-driven immunosuppression as well as selective biological effects of different Trp-metabolites such as kynurenine, quinolinic acid or kynurenic acid.

E7: Influence of acute stress on bacterial defense

Graduate students: Michael Nielson, Friedemann Maess
Tutor: Claus-Dieter Heidecke,
It has been shown that acute perioperative stress leads to postoperative immune suppression. This project aims to elucidate the complex alterations of two forms of acute stress induced by acute psychological stress (acoustic and restraint stress) or LPS (E7.1) as well as by perioperative stress (surgical irrigation of the peritoneal cavity) (E7.2). The project will measure effector functions of the innate and adaptive immune system in the context with neuroendocrine regulatory pathways such as HPA axis resonses as well as sympathetic, parasympathetic, serotonergic and indoleaminergic activities.