Acceptance of Skin Allografts in Pigs by Portal Venous Injection of Donor Bone Marrow Cells

Various attempts have been made to induce persistent tolerance across major histocompatibility complex (MHC) barriers, these methods ultimately to be applied to organ transplantation in humans. Tolerance is generally induced by three mechanisms: clonal deletion, suppression, and clonal anergy. Clonal deletion, which occupies the main part of self-tolerance, is induced by reconstituting lethally irradiated recipients with donor hematolymphoid cells; we have previously reported that successful organ allografts can be achieved by carrying out bone marrow transplantation in conjunction with organ allografts. 1,2 Some improvements on this strategy have recently been made using monoclonal antibodies against T cells to reduce radiation doses 3 or areas. 4,5 However, it has recently been noted that potent and persistent tolerance is induced using clonal anergy and suppression mechanisms. 6,7 Anergy to organ allografts was induced by CD28-B7 blockade 8–10 or the expression of “protective genes,” and the suppression of graft-reactive Th1 cells was maintained by the Th2 counterpart expanding after the anergy induction. The administration of foreign cells using the portal vein (PV) has been reported to induce donor-specific tolerance across major, 11–16 minor, 17 and xeno 18 histocompatibility complex barriers. In mice, we recently analyzed the mechanism by which the donor-specific tolerance is induced after the PV injection and found that it is due to the induction of clonal anergy in the CD8+ cells of the recipients. 19,20 In the present study, using the PV injection and skin grafts in pigs, we report a single-day protocol for the induction of potent and persistent tolerance across MHC barriers.