Current Status of Cardiac Xenotransplantation: Report of a Workshop of the German Heart Transplant Centers, Martinsried, March 3, 2023

Abstract

This report comprises the contents of the presentations and following discussions of a workshop of the German Heart Transplant Centers in Martinsried, Germany on cardiac xenotransplantation. The production and current availability of genetically modified donor pigs, preservation techniques during organ harvesting, and immunosuppressive regimens in the recipient are described. Selection criteria for suitable patients and possible solutions to the problem of overgrowth of the xenotransplant are discussed. Obviously microbiological safety for the recipient and close contacts is essential, and ethical considerations to gain public acceptance for clinical applications are addressed. The first clinical trial will be regulated and supervised by the Paul-Ehrlich-Institute as the National Competent Authority for Germany, and the German Heart Transplant Centers agreed to cooperatively select the first patients for cardiac xenotransplantation.

Fig. 1

Mechanisms of hyperacute xenograft rejection and strategies to overcome them. Created with BioRender.com.

Fig. 2

Activation of protein C by the thrombin–thrombomodulin complex after allogeneic (top) and xenogeneic transplantation (bottom). EPCR, endothelial protein C receptor; PC, protein C; PCa, activated protein C; TBM, thrombomodulin; Va, activated factor V; VIIIa, activated factor VIII. Created with BioRender.com.

Fig. 3

Auckland Island pigs in the Center for Innovative Medical Models (CiMM; www.lmu.de/cimm/ ) at LMU Munich.

Fig. 4

Flowchart to achieve optimal donor–recipient-combinations for clinical xenotransplantation. Cross-matching of sera from potential recipients should be performed by using cells from TKO pigs lacking αGal, Neu5Gc, and Sd(a). Negative cross-match: Organs from TKO donor pigs combined with additional genetic modifications will be used as previously explained. In case of a positive cross-match, further characterization of antipig antibodies will be required. Recipients expressing anti-SLA antibodies may be transplanted with organs from SLA-I/II knockout pigs or pigs expressing mutated SLA to avoid antibody binding (both on “TKO plus” platform). Cross-matching may be complemented by HLA–SLA matching to identify donor–recipient combinations with low level T cell reactivity.