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The Role of Necroinflammation in Preclinical Kidney Xenotransplantation

Institution: Universitätsklinikum Carl Gustav Carus, Dresden
Applicant: Prof. Dr. med. Andreas Linkermann
Funding line:
Translational Research
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Co-applicants:

Dr. rer. nat. Konrad Fischer (TU München)
Prof. Dr. vet. med. Rabea Hinkel (Deutsches Primatenzentrum, Göttingen)
Dr. med. Dionysios Koliogiannis (LMU München)
 

Project partner:

Prof. Stig Steen and Prof. Michael Olausson, Lund University, Sweden


Project:

Necrotic cell death as defined by plasma membrane rupture (necrosis) is a genetically determined and tightly regulated process, best investigated in the pathways of necroptosis, pyroptosis and ferroptosis. Xenotransplantation of any organ involves necrosis of parenchymal cells, which inevitably results in the release of damage-associated molecular patterns (DAMPs) that trigger an immune response in a process defined as necroinflammation. In addition to necroinflammation, xenotransplantation triggers non-necrotic inflammation due to species incompatibility. It is currently unclear to which extent these distinct inflammatory stimuli contribute to xenotransplant rejection.

We and others identified biomarkers of necroptosis (pMLKL), pyroptosis (cGSDMD) and ferroptosis (peroxidized phosphatidylethanolamine (PE)) that allow to directly detect these pathways in xenografts. Identification of the relative contribution of necrotic pathways to xenograft damage, therefore, will allow identification of the relative contribution of these pathways during the xenotransplantation procedure. Unique multi-modified pigs expressing human complement regulator genes (hCD46, 55, 59), anti-inflammatory, anti-apoptotic genes (HO-1, A20) and lacking gal-epitopes will serve as organ donors. Objectives of our proposal are to identify rejection reactions and other causes of xenoorgan malfunction. This will enable us to make informed decisions about necessary interventions or additional modifications to the donor-organ in order to achieve consistent successful renal xenotransplantation and to elaborate efficacy studies leading to clinical application.

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