40 years of heart transplantation and the DFG‐Transregio Research Group Xenotransplantation

Today, organ transplantation represents a well‐established and effective therapy of terminal organ failure revealing high actuarial survival rates. Unfortunately, the enormous potential of organ transplantation cannot be tapped due to the significant gap between organ demand and organ donation. Current statistics of the International Society of Heart and Lung Transplantation prove a continuity of depressed numbers of transplantations performed per year since the late nineties. To counteract the persisting severe shortage of human organs in Germany and worldwide suboptimal donor organs and/or organs from older donors were accepted. Both the acceptance of inferior organs and the implementation of the Transplantation Law (in Germany in 1997) could not answer this problem. Increasing the donor rates emerge difficult to achieve and will ultimately result in numbers which are not sufficient. The improvement of transplant results by e.g. a less nephrotoxic immunosuppression, or the generating of hyporeactivity or even tolerance is an additional aim important to achieve. Alternative techniques to answer the tremendous organ shortage might be the differentiation of embryonic stem cells or the reprogramming of adult stem cells as a virtually unlimited source for cell replacement to treat degenerative diseases or traumatic tissue injury. Yet, disadvantages such as ethical issues and the generation of tumorigenic cells should not be underestimated. A cellular therapy by the injection of undifferentiated bone marrow (CD133 + stem/progenitor) cells into the myocardium in combination with or without aortocoronary surgery for chronic ischemic heart disease as well as cells from the amniotic fluid (Wharton's jelly) might also represent possible future solutions to the organ deficit but still are far from a functional substitution of the human heart. Until now there is no in‐all implantable mechanical heart assist device which is able to completely and permanently replace the human organ and provide a quality of life comparable to that after allotransplantation. In contrast, xenotransplantation, using porcine organs for human transplantation, offers a potential solution to the world‐wide lack of donor organs. The advantages of xenotransplantation are an unlimited disposability of donor organs, an elective transplantation with a subsequent reduction of ischemic time and the possibility of a pre‐operative start of the immunosuppressive therapy of the recipient. Harmful effects of the brain death of the donor to the donor organ could be excluded. Finally, genetic modifications of compatible xenografts could be made. Substantial progress of the research in the field of xenotransplantation has been possible thanks to the introduction of organs from genetically engineered pigs transgenic for human complement regulatory proteins [e.g. human decay accelerating factor (hDAF/hCD55), human membrane cofactor (hMCP/hCD46), and human membrane inhibitor of reactive lysis (hMIRL/hCD59)]. Using an effective and persistent depletion of preformed cytotoxic anti‐Galα(1,3)Gal antibodies (IgM and IgG) by a Galα(1,3)Gal therapeutic (e.g. GAS914, TPC) in combination with these transgenic pigs hyperacute rejection can be avoided successfully. During the early phase after transplant acute vascular rejection triggered by induced anti‐Galα(1,3)Gal antibodies can be controlled. Several groups developed pigs which lack the Galα(1,3)Gal xenoantigen. Studies on xenotransplantations performed with homozygous alpha(1,3)‐galactosyltransferase gene knockout pigs demonstrated that these modified pig organs offer some progress in terms of graft survival. Thus, the major xenoantigen Galα(1,3)Gal is no longer an unsurmountable immunological barrier preventing transplantation of pig organs into humans. Acute vascular rejection, however, remains as a major hurdle to clinical application of xenotransplantation due to cytotoxic anti‐pig antibodies of other specificity than Galα(1,3)Gal. Furthermore, humoral factors are not the only players in xenograft rejection. Primate anti‐pig cellular immunity is defined by multifocal lymphocytic infiltrates, with morphologic evidence of direct tissue damage. Pre‐requisites for the clinical use of xenotransplantation are PERV‐C (porcine endogenous virus C) free animals using a PERV knock down (si‐RNA) technique. Multitransgenic αGalT‐KO [alpha(1,3)‐galactosyltransferase knockout] pigs additionally expressing human complement regulator proteins, and human anticoagulants (e.g. human thrombomodulin) are necessary to reliably prevent not only hyperacute rejection as the first immunological barrier, but also acute vascular rejection at its beginning, when serum cytotoxicity to the pig heart appears to be predominantly Galα(1,3)Gal‐specific. Further co‐stimulation blockade (e.g. PD‐1L, CTLA‐4‐Ig), HLA‐E [protection against human NK (natural killer)‐cells], or haemeoxygenase‐1 (defense against disseminated intravascular coagulation) will help to suppress acute vascular and acute cellular xenograft rejection. Special pathogen free (SPF) units and breeding conditions of pig organ donors limit the risk of microbial contamination by most pathogens liable to be transmitted from a pig graft to a human recipient. Our DFG‐(German Research Council) Transregio Research Group Xenotransplantation assembles an interdisciplinary group of leading German laboratories incl. biotechnologists, immunologists, virologists, and surgeons with vast experimental expertises in the field of experimental and clinical allotransplantation and experimental xenotransplantation. The first clinical goal of xenotransplantation is xenogeneic tissue transplantation such as the transplantation of porcine islet cells (αGalT‐KO (?), CTLA‐4‐Ig expression) in diabetic patients with hypoglycemic attacks as well as porcine cornea, porcine cardiomyocytes and porcine heart valves, possibly porcine bones and teeth (?). Thereafter, xenogeneic organ transplantation starting with the more promising use of kidneys and hearts is the definitive clinical goal. In summary, clinical heart transplantation represents an accepted method of end‐stage heart failure with an outdated “standard immunosuppression” and the need of an individualized immunosuppression adjusted to the specific needs of the individual patient. The organ shortage remains the main obstacle of the heart transplantation, and other organ transplantation, respectively. In the near future, xenotransplantation will be possible!