Glaxo/MRS Young Investigator Prize. Xenotransplantation: immune barriers beyond hyperacute rejection

1. The use of organs from animal donors (xenotransplantation) is a potential solution to the chronic shortage of allogeneic organs and currently the pig is thought to be the most suitable donor for man. However, porcine organs are rejected rapidly by a vascular process called hyperacute rejection which has so far prevented clinical xenotransplantation. Although it is likely that this barrier will be overcome in the near future by the application of novel strategies, probably involving the use of organs from transgenic pigs, data from animal models indicate that multiple other immune mechanisms will contribute to the rejection of xenografts. 2. We have described two aspects of these immune mechanisms. First, the phenomenon of 'accommodation', whereby xenografts acquire in vivo resistance to vascular rejection, has been explored in an in vitro model utilizing immortalized porcine endothelial cells. The results indicate that human anti-pig antibodies induce a concentration-dependent and time-dependent change in porcine endothelial cells compatible with the development of accommodation. 3. Secondly, the in vitro human anti-porcine T-cell response has been documented in detail, with particular emphasis on quantitative and qualitative comparisons with the in vitro T-cell alloresponse. The results of this work, which indicate that the response to porcine xenografts is likely to be significantly stronger than that against allografts, have important implications for the level of conventional immunosuppression that may be necessary to prevent xenograft rejection, and provide an important basis for the development of strategies to promote xenograft-specific immunosuppression and tolerance.