Collaborative research funded by the German Research Foundation
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
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)
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
Contact within the Faculty: Prof. Dr. Christoph Becker, Department of Medicine 1
Contact within the Faculty: Prof. Dr. A. Mackensen, Dr. M. Aigner, Department of Medicine 5
Contact within the Faculty: Prof. Dr. A. Bosserhoff, Dr. S. Kuphal, Institute of Biochemistry
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
Contact within the Faculty: Prof. Dr. Markus Neurath, Department of Medicine 1