Functional Relevance of the TRAIL-TRAIL Receptor System for the Outcome of Vascularized Grafts

• Applicants: Professorin Dr. Katharina Beyer; Professorin Dr. Katja Kotsch, Ph.D.
• Subject Area: General and Visceral Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508048437

The tumor necrosis factor (TNF)a related apoptosis-inducing ligand (TRAIL) has been extensively described in the context of tumor research. In humans, two TRAIL receptors are currently known that possess a functional death domain and thus can induce apoptosis: TRAIL receptor 1 (TRAIL-R1, DR4) and TRAIL receptor 2 (TRAIL-R2, DR5), whereas in mice only DR5 exists, which is not structurally identical to the human DR5 receptor. Apart from its classical role in apoptosis induction, TRAIL also modulates the immune system as already demonstrated in chronic and autoimmune diseases. For instance, following engagement of TRAIL with its receptors, TRAIL contributes to the regulation of the T cell compartment by e.g. the increased death of autoreactive T cells and increasing the immunosuppressive capacity of regulatory T cells. Apart from its influence on T cells, TRAIL plays also a major role for Natural Killer (NK) cells, as human liver NK cells can upregulate TRAIL, giving them the capacity to kill hepatocytes that express DR5. Consequently, TRAIL is involved in a plethora of various mechanisms including tolerance induction or limitation of inflammation. Since these mechanisms also play a role in the immune system’s response towards allogeneic transplants, the functional importance of TRAIL in the setting of solid organ transplantation (SOT) needs to be established. Our preliminary data already demonstrate that TRAIL and its receptor DR5 are downregulated on graft-derived T and NK cells as a consequence of the alloimmune response post murine kidney transplantation. More importantly, in the clinical setting TRAIL expression was found to be clearly expressed at lower levels on peripheral blood-derived T cells derived from hemodialysis and kidney transplanted patients. The aim of the present project is therefore to investigate the importance of the TRAIL–TRAIL receptor system in the context of SOT. For this purpose we will make use of TRAIL-deficient mice in order to investigate the impact of TRAIL on the cellular composition of potential kidney grafts by a comprehensive phenotypical characterization of various immune subsets. Moreover, we intend to investigate the role of the TRAIL-TRAIL receptor system for the outcome of vascularized grafts in experimental heart and kidney transplantation and finally we will characterize the expression of TRAIL and its receptors in patients diagnosed with end-stage kidney disease (ESRD) and kidney transplanted patients. Our expected results will contribute towards a better understanding of this yet unrecognized pathway in the setting of SOT, finally leading to new concepts on modulating the immune response towards an improved allograft survival.

• DFG Programme: Research Grants