Skin tolerance: in search of the Holy Grail

In 1943, Gibson and Medawar opened the modern era of transplantation research with a paper on the problem of skin allograft rejection. Ten years later Billingham, Brent and Medawar demonstrated that it was possible to induce selective immune acceptance of skin grafts in mice, a state of tolerance. After over six decades, however, the precise mechanism of skin allograft rejection remains still ill-defined. Furthermore, it has not been possible to achieve reliably clinical tolerance allowing the widespread application of skin allotransplantation techniques. The first successful applications of skin allotransplantation have included the hand and face. However, complications from the chronic immunosuppression regimens limit the application of these techniques. Induction of tolerance to skin (and the other tissues in the allograft) would be the most effective way to overcome all these difficulties, but this is yet to be achieved reliably, stimulating some to look for other ways to surmount the current limitations. This paper summarizes alternatives to enlarge the scope of skin allotransplantation techniques, current understanding of mechanisms of skin rejection, and the utility and limitations of animal models used to study skin rejection and tolerance induction. Finally, manipulation strategies to achieve skin tolerance are outlined.