Future
prospects
The two major problems in organ transplantation are:
Chronic graft rejection and the side effects of
nonspecific immunosuppression
• the shortage of organs for transplantation.
A long-standing goal in organ transplantation has been the development
of strategies for inducing specific immunological tolerance. Transplantation
tolerance would eliminate the need for long-term nonspecific immunosuppressive
agents, leaving the immune system intact for defence against infection. It has
long been possible to induce transplant tolerance in experimental animals by a
variety of preconditioning regimens that often involve antigen pretreatment
schedules. So far, however, there is no clinically applicable strategy for
inducing transplant tolerance.
The demand for human organs for transplantation is so
great that cadaveric donors cannot ever satisfy it. Many consider that the
solution is to perfect xenotransplantation, and there is general agreement that
the pig is the most suitable source of xenogeneic organs. However, all humans
have preformed antibodies directed against carbohydrate antigens expressed by
pig organs and these result in hyperacute rejection. The dominant carbohydrate
antigen responsible is galcL-1,3-gal. Progress has been made towards
circumventing hyperacute xenograft rejection, for example by using organs from
pigs that have been made transgenic for human complement regulatory proteins.
However, such organs are still rejected within a few weeks by primates, despite
the use of potent immunosuppressive agents. In addition to the complex
immunological problems posed by xenotransplantation, there is a risk that pig
organs may transmit infectious agents, and there is particular concern about the
risks posed by porcine endogenous retrovirus (PERV). Finally, there are
unanswered questions regarding the extent to which pig organs are able to fulfil
the physiological demands required of them after transplantation into a human.