Recipient natural killer cells alter the course of rejection of allogeneic heart grafts in rats.

Rejection of solid organ grafts is regarded to be dependent on T cell responses. Nonetheless, numerous studies have focused on the contribution of NK cells in this process, resulting in contradictory theories. While some conclude that there is no participation of NK cells, others found an inflammatory or regulative role of NK cells. However, the experimental settings are rarely comparable with regard to challenged species, strain combinations or the nature of the graft. Thus, clear definition of NK cell contribution might be impeded by these circumstances. In this study we performed heterotopic heart transplantation (HTx) in rats, choosing one donor-recipient-combination leading to a fast and a second leading to a prolonged course of graft rejection. We intervened in the rejection process, by depletion of recipient NK cells on the one hand and by injection of activated NK cells syngeneic to the recipients on the other. The fast course of rejection could not be influenced by any of the NK cell manipulative treatments. However, the more prolonged course of rejection was highly susceptible to depletion of NK cells, resulting in significant acceleration of rejection, while injection of NK cells induced acceptance of the grafts. We suggest that, depending on the specific setting, NK cells can attenuate the first trigger of immune response, which allows establishing the regulatory activity leading to tolerance of the graft.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.