Recent Progress in Xenotransplantation, with Emphasis on Virological Safety.

Xenotransplantation is a new technology that may help to overcome the shortage of human tissues and organs available for the treatment of tissue and organ failure. Remarkable progress has recently been made in this field. First, understanding of the mechanisms of immunological rejection, mainly of the hyperacute rejection, allowed generating numerous genetically modified pigs to overcome rejection. Second, based on these genetically modified animals and new immunosuppression regimens, long-term survival of non-human primate recipients of heart, kidney, and islet cell cells has been reported. And third, potential zoonotic microorganisms have been identified in pigs and sensitive methods to detect them have been generated. In 2 clinical trials treating diabetic patients with porcine islet cells, no porcine microorganisms were transmitted to human recipients. Furthermore, strategies to eliminate potentially zoonotic microorganisms from donor pigs in order to prevent transmission to the recipients have been developed, including designated pathogen-free (DPF) breeding. In addition, strategies to prevent transmission of porcine endogenous retroviruses (PERVs) have been developed, including a knockout of all proviruses in the pig genome by gene editing. PERVs are integrated in the genome of all pigs and therefore they cannot be eliminated by DPF breeding. Since they are able to infect human cells, they represent a special risk in xenotransplantation. Despite the achievements, some problems remain: numerous genetically multi-modified pigs have been generated without fully evaluating their advantage, and microbiological screening of pigs to be used for transplantations and elimination of pathogenic microorganisms from the donor pigs are still not satisfactory.