Collaborative research funded by the German Research Foundation

Inflammation is the key response strategy of the body to react to tissue stress and damage. The activation of the immune system related with inflammatory reaction need strict controls. In this context particular importance is attached to the molecular checkpoints, which are responsible to stop inflammatory reaction in time and finally for its resolution. In fact, there is still very limited knowledge on the mechanisms of resolution, however they are of central relevance for pathogenesis and therapy of inflammatory chronic diseases.

The collaborative research center (SFB 1181) initiative is a joint project of the faculties of medicine and natural science of the FAU and the Max Planck Institute for the Sciences of Light. Among 19 scientific projects serves to unravel the molecular checkpoints, which decide about resolutions respectively chronicity, are classical and innovative instruments for gender equality, state-of-the art training programs and networking integrated in this program.

Contact within the Faculty: Prof. Dr. G. Schett, Department of Medicine 3

B cells are an important part of the human immune system. If pathogens invade the body, antibodies are secreted by these types of cells that fight the pathogens. The scientists of the Transregional Collaborative Research Center examine the mechanisms how B cells produce antibodies and secrete them. The aims of the scientists are how immune responses are triggered, how a B cell memory is formed, and how long-lasting levels of antibodies are maintained. A second aim of the consortium (TRR 130) is to analyze dysfunctions of the immune system which can lead to a process of autoantibodies attacking the own body. These reactions can result in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis. The planned research is aimed to understand the mechanisms of these diseases and to develop new therapies. Participating institutions are: FAU (speaker university), Freiburg University, Charité Berlin, Deutsches Rheuma-Forschungszentrum Berlin, Max Planck Institute for Infectious Biology, Berlin, and Göttingen University.

Contact within the Faculty: Prof. Dr. H.J. Jäck, PD Dr. D.A. Mielenz (Division of Molecular Immunology), Prof. Dr. D. Vöhringer (Division of Infection Biology)

In the Collaborative Research Center Transregio 221 (TRR 221), immunologists and scientist of the universities and the university hospitals in Erlangen, Regensburg, and Würzburg research ways to secure allogeneic future stem-cell transplantation by avoiding relapses and degrading transplantation complications.

Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment option for patients with high-risk leukemia and lymphoma and for some inherited or acquired hematopoietic deficiencies. Around half a million transplantations have been performed to date and approximately 28 million voluntary stem cell donors are currently registered world-wide. The curative potential of allo-HSCT is based on the replace­ment of the patient´s hematopoiesis by hematopoietic stem cells derived from a healthy donor and the immunologic eradication of residual patient hematopoietic cells by co-transplanted lymphocytes. This graft-versus-hematopoiesis reaction is mainly mediated by alloreactive donor T cells and affects also malignant hematopoietic cells, thereby evoking potent graft-versus-leukemia / lymphoma (GvL) effects. Although allo-HSCT offers a unique chance to rescue patients with otherwise incurable hematologic malignancies, still around one quarter of allo-HSCT recipients develop disease relapse or progression after transplantation. Thus, there is an urgent need to better understand and ultimately strengthen GvL responses to prevent tumor escape. However, GvL-promoting strategies carry the inherent risk of inducing graft-versus-host disease (GvHD), where donor T cells attack and damage non-hematopoietic tissues. The efficient prevention and treatment of severe GvHD is a pivotal prerequisite to benefit from allo-HSCT and its potent GvL effects. Hence, the elucidation of basic mechanisms in tissue-directed graft-versus-host responses is essential to reduce the high treatment-related morbidity and mortality in allo-HSCT. GvHD-free allo-HSCT is then an ideal immunotherapy platform to boost GvL responses for the cure of patients, including those with residual disease or relapse after transplantation.

Within TRR 221 innovative immune modulation strategies will be investigated to separate GvHD from GvL effects in order to enhance the safety and efficacy of allo-HSCT in the future. Briefly, the projects in area A explore T cell redirection tools (i.e. T cell receptors, chimeric antigen receptors, minor histocompatibility antigens, multi-specific antibodies) for the augmentation of hematopoiesis-specific GvL activity, and examine the reactivation of silenced GvL responses by checkpoint inhibition and through enhanced metabolic “fitness” of donor immune cells. The projects in area B investigate cell signaling pathways (i.e. TNFR2, CD28, Wnt, NFAT, IL-7R/Batf/CSF2) and immune regulatory/suppres­sive cells and networks including regulatory T cells, mesenchymal stromal cells and dendritic cells to prevent and/or treat acute and chronic GvHD. They also study the modulation of GvHD-promoting co-factors such as tissue inflammation, microbiome alterations, epithelial and endothelial damage for effective prophylaxis and therapy of severe GvHD. Promising strategies in GvL projects will be evaluated with respect to their influence on GvHD (and vice versa) and all participating institutions support translational studies evolving from the TRR 221 projects if considered sufficiently robust for clinical testing.

Contact within the Faculty: Prof. Dr. A. Mackensen, Department of Medicine 5

This newly established transregional Collaborative Research Center deals with the pathogenesis of inflammatory bowel diseases and future therapeutic approaches. A scientific focus is on the interaction between the intestinal barrier and the immune system in the bowel wall. Involved partners are the Charité and the German Rheumatism Research Center in Berlin (DRFZ).

Contact within the Faculty: Prof. Dr. Christoph Becker, Department of Medicine 1

The clinical research unit KFO 262 “Tumor metabolism as modulator of immune response and tumor progression”, funded by the DFG, started in September 2011 and was renewed in September 2014. The aim is to clarify how to best target these unique metabolic dependencies of tumor cells for therapeutic benefit and to identify drugs and diagnostic biosignatures for cancer therapy,.

Contact within the Faculty: Prof. Dr. A. Mackensen, Dr. M. Aigner,  Department of Medicine 5

Aim of the research unit (FOR 2127) is a systematic analysis of systemic cancer progression. We will focus on evolutionary processes that drive colony formation and growth of a metastasis as well as the development of drug resistance.

Contact within the Faculty: Prof. Dr. A. Bosserhoff, Dr. S. Kuphal, Institute of Biochemistry

The scientific aims of the research unit (FOR 2149) revolve around the central questions in adhesion-GPCR biology: Which signals do adhesion-GPCR perceive? How do they transduce these signals into the cell? What happens when adhesion-GPCR signaling is compromised? These questions are targeted from different angles encompassing physiology, biochemistry, structural biology, pharmacology, and nanoscopic imaging techniques.
Importantly, the strengths of invertebrate and vertebrate models will be used to synergize efforts in linking molecular steps in adhesion-GPCR signaling to physiological processes governed by these unusual receptors. Specific care is dedicated to interlock the projects not only methodologically, but especially at the conceptual level to facilitate the extraction of general principles of adhesion-GPCR signaling.

Contact within the Faculty: Prof. Dr. F.B. Engel, Division of Nephropathology

Since July 2016, the DFG has been funding the research group on colorectal cancer with 3.5 million euros for three years. Scientists from the Universities of Erlangen, Frankfurt, and Regensburg jointly investigate fundamental mechanisms for the development of colorectal cancer (FOR 2438) . The scientists of FOR 2438 are investigating the complex molecular and cellular interrelations in the micromilieu of colorectal cancer by means of complementary approaches in order to derive new therapeutic concepts from these.

Contact within the Faculty: Prof. Dr. Markus Neurath, Department of Medicine 1

The new DFG research group FOR 2886 (PANDORA) aims to better investigate and understand the causes of rheumatoid arthritis (RA). The focus here is especially the influence that the natural bacterial flora or the microbiome as well as a number of environmental factors (including nutrition and salt consumption) exerts on our immune system and thus can cause or even prevent a break in immune tolerance. In addition, it should be investigated in more detail why RA breaks out only in a part of the people who have a corresponding autoimmune reaction, while other affected people remain asymptomatic for years. A better understanding of the causative molecular and cellular relationships would not only enable new, more effective and individualized therapeutic strategies, but would also open for the first time options to cure this disease. Accordingly, it is also planned to perform a first study in which a sequential combination of several therapeutic protein molecules (biologics) should reprogram the immune system (directed against one’s own body) in RA patients.

Contact within the Faculty: Prof. Dr. G. Krönke and Dr. M. Zaiss, Department of Medicine 3