Solid organ xenotransplantation: Progress, promise and regulatory issues

Abstract

Xenotransplantation, the process of transplanting live cells, tissues and organs from one species into another, is an emerging novel area in medicine. It is proposed as a treatment for human end-stage organ failure and for other applications such as, for example, the treatment of neurodegenerative and liver disorders, meeting the large demand for donor organs. The pig is considered to be the most suitable donor species. However, the rejection of a pig transplant is much more severe and multifactorial compared with that of a human graft and involves almost all branches of the human immune system. Major rejection mechanisms include complement-mediated rejection, antibody-mediated rejection and cellular rejection. Prevention of rejection requires not only improved immunosuppressive agents, but also innovative approaches including the genetic modification of the pig donor by which organs become more easily acceptable, and the modulation of the human recipient's immune system so that it tolerates the xenograft without the need of extensive immunosuppression. Regarding safety, concerns have been raised on the potential risk of transmission of infectious microorganisms by a pig transplant to a human patient, and subsequent spread of infectious microorganisms into the population by an infected individual. This in particular concerns porcine endogenous retrovirus: to date intensive research has shown no evidence that this virus is transmitted in vivo from pig to humans; also a miniature swine line has been identified which does not give detectable in vitro transmission to human cells. Based on concerns on xenotransplantation, especially the safety of porcine-to-human transplants, many countries in Europe, the USA and Canada have instituted stringent policies for the development of xenotransplantation products, which include guidelines and regulations of clinical trials and additionally include public discussions on the issues associated with xenotransplantation. Based on these initiatives of regulatory authorities, xenotransplantation could advance towards a clinical application by a closely monitored stepwise approach. It is expected that advances in preclinical research during the coming years will give a further basis for such a stepwise development from a promising tool into a new well-accepted clinical entity.