Role of Innate Lymphoid Cells (ILC) in Solid Organ Transplantation

• Applicant: Professorin Dr. Katja Kotsch, Ph.D.
• Subject Area: General and Visceral Surgery ; Nephrology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428193823

Over the past decades the progress in immunosuppressive medication resulted in substantial improvement of short-term allograft survival in solid organ transplantation (SOT). However, an improvement of long-term function is still an unmet medical goal. Due to the progressing shortage of available transplants, the utilization of marginal organs from expanded criteria donors (ECD) has been implemented into clinical routine. Donor age is the most important risk factor defining an ECD organ, with donor brain death (BD) and ischemia-reperfusion injury (IRI) representing contributing factors for inferior organ quality. Recently, we demonstrated that human senescent kidney grafts are characterized by high expression of the NK-cell-associated cytotoxicity receptor NKG2D, being associated with inferior graft function. We further demonstrated that donor BD results in a significant organ-specific redistribution of innate lymphocytes. This family has considerably expanded with the discovery of innate lymphoid cells (ILCs), a multifaceted group of mainly tissue resident cells involved in desired and undesired immune responses. In the context of SOT, the role of ILC has not been comprehensively studied so far. Our preliminary data demonstrate that potentially regenerative type2 ILC (ILC2) reside within the healthy kidney, but disappear after experimental kidney transplantation, whereas potentially pro-inflammatory NK cells populate the graft. We further generated first data pointing towards a redistribution of ILC subsets in aged versus young organs. In the present project, we will examine how ILC biology is impacted by the transplantation-associated risk factors age, BD and IRI and how these risk factor induced ILC alterations relate to allograft outcome. As SOT entails the confrontation of both donor and recipient immunity, we will monitor the intra-organ composition and function of both donor- and recipient-derived ILCs by studying their migration to and persistence in the allograft as well as to distal organs. To decipher whether the transplantation-associated redistribution of donor or recipient ILCs is associated with altered graft function, we will therapeutically interfere with ILC migration capacity and analyse graft outcome. Based on previous studies suggesting a role for Interleukin-33 and Interleukin-25 in the regeneration following kidney damage, we will address whether treatment of the donor or recipient can reduce tissue injury post-transplantation and whether this process is mediated by regenerative ILC2. Our studies will be complemented by the analysis of human ILC samples before transplantation as well as in perfusates following machine perfusion for organ reconditioning. In summary, we will for the first time comprehensively study the role of ILC in the context of solid organ transplantation and test strategies to therapeutically manipulate ILC biology towards tissue homeostasis and regeneration, thereby improving graft function.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1937: Innate Lymphoid Cells