Novel Input for Xenotransplantation by Revisiting Landmark Preclinical and First-in-Man Studies with Innovative Methodologies

• Applicants: Professor Dr. Nikolai Klymiuk; Dr. Daniel Reichart
• Subject Area: Cardiac and Vascular Surgery ; Immunology ; Veterinary Medical Science
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567667355

Fundamental progress in immune suppression (IS) of recipients and genetic modification (GM) of donor animals has transformed heart xenotransplantation (HXT) from a revolutionary therapeutic concept into clinical application. Although feasibility in the first cases was demonstrated, it became clear that further refinement needed to develop HXT into an even safer, more tolerable and with subsequent excellent long-term clinical results. It is highly likely that the remaining problems in HXT will not be resolved by single IS or GM measures. Instead, sustained progress needs to lead to a better and broader understanding of the complex physiological and pathophysiological processes within the xenografts and recipient´s body. Hypothesizing that systematic and unbiased in-depth examination of tolerated and rejected xenografts will reveal driving and amplifying forces that determine about the faith of a graft, we will here explore tissue and blood samples from an unprecedented set of 19 pre-clinical and 2 clinical cases. Aiming at previously unknown key players in HXT rejection and, equally important, regulatory processes that support graft tolerance, we will characterize xenografts by using single cell technologies, investigate the barriers between species and explore relevant mechanisms with complementary molecular and immunological assays. The ambitions of this project require interdisciplinary and collaborative research for several reasons. Translating the complex molecular pattern within a tissue context into a picture of causal processes and by-standing effects require validation in well-defined cellular settings. Such assays will also allow us to identify measures to counterbalance processes that affect graft function. This is particularly important for regulatory pathways that suffer impaired communication between cells across species barriers. Further, physiological differences in the immune biology of donor pigs and baboon or human recipients may contribute to graft loss and impede the predictability of pre-clinical studies for clinical cases. Similarly, pre-clinical work involving healthy primate recipients only insufficiently reflects the potential immunological pre-conditioning in human HXT recipients. For a better understanding of immunological commonalities and peculiarities in experimental models and clinical settings, we will therefore embed the signatures of tolerated and rejected xenografts in a cross-species immune cell atlas of the three species, involving the immunological profiles of waiting list patients. Altogether, we will use data from precious groundbreaking pre-clinical and clinical studies to decipher remaining hurdles in HXT and test potential counter-acting measures to eventually define promising pre-evaluated combinations of improved IS and novel GM in future HXT.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Cooperation Partner: Professor Dr. Jörg Seebach