IXA Honorary Member Lecture, 2017: The long and winding road to tolerance.

The last 15 years or so have seen exciting progress in xenotransplantation, with porcine organ grafts surviving months or even years in non-human primates. These advances reflect the application of new scientific knowledge, improved immunosuppressive agents, and genetic engineering. The field has recently enjoyed a renaissance of interest and hope, largely due to the exponential increase in our capacity to genetically engineer porcine source animals. However, immune responses to xenografts are very powerful and widespread clinical application of xenotransplantation will depend on the ability to suppress these immune responses while preserving the capacity to protect both the recipient and the graft from infectious microorganisms. Our work over the last three decades has aimed to engineer the immune system of the recipient in a manner that achieves specific tolerance to the xenogeneic donor while preserving otherwise normal immune function. Important proofs of principle have been obtained, first in rodents, and later in human immune systems in "humanized mice" and finally in non-human primates, demonstrating the capacity and potential synergy of mixed xenogeneic chimerism and xenogeneic thymic transplantation in tolerizing multiple arms of the immune system. Considering the fact that clinical tolerance has recently been achieved for allografts and the even greater importance of avoiding excessive immunosuppression for xenografts, it is my belief that it is both possible and imperative that we likewise achieve xenograft tolerance. I expect this to be accomplished through the availability of targeted approaches to recipient immune conditioning, understanding of immunological mechanisms of tolerance, advanced knowledge of physiological incompatibilities, and the availability of inbred miniature swine with optimized use of genetic engineering.