Adhesive functions of both chains of VLA-integrins are not fully conserved across the human-porcine species barrier: implications for xenotransplantation

Abstract

A possible solution to the shortage of organs for transplantation would be the use of swine as source animals. As current immunosuppressive protocols cannot prevent rejection of these organs, super-selective immunosuppression or the induction of donor-specific central tolerance represent two promising approaches. Central tolerance induction involves bone marrow transplantation, and depends on intrathymic deletion of donor reactive host cells by donor antigen-presenting cells. In super-selective immunosuppression, the aim would be to block specific adhesive interactions on one species side only, leaving the other species side unaffected. As both processes depend on the interaction of adhesion molecules with their ligands, we investigated whether the beta1-integrins, which play roles in hematopoiesis as well as in rejection, can successfully interact across the swine-to-human species barrier. We employed static cell-to-extracellular protein and cell-to-cell adhesion assays, using different cell types and monoclonal antibody as well as peptide-fragments to analyze conservation of cross-species adhesive interactions. We found that porcine and human cells interact differently with their cross-species ligands than their own and that the adhesive function of the beta1-chain does not seem to be fully conserved across the species barrier. Integrin functions are not fully conserved across the pig-to-human species barrier. While the development of multi-transgenic pigs, whose integrins interact with human ligands in a more ''human-like'' manner may be necessary to facilitate tolerance induction, these facts give rise to new possibilities concerning super-selective immunosuppression.