DISCORDANT XENOGENEIC NEONATAL THYMIC TRANSPLANTATION CAN INDUCE DONOR-SPECIFIC TOLERANCE

The limited supply of human organs for transplantation necessitates th e development of methods leading to acceptance of xenografts, To avoid the hazards of the high-dose chronic immunosuppressive pharmacotherap y which would otherwise be required for successful xenografting, it wo uld be desirable to induce permanent tolerance to xenogeneic donors. W e have recently demonstrated that xenogeneic donor-specific tolerance can be induced by transplanting fetal pig thymic and hematopoietic tis sue into thymectomized, T cell-depleted, and natural killer-cell-deple ted mice, or into natural killer cell-depleted nude mice. We have now extended these studies by replacing fetal tissue with neonatal pig thy mic and hematopoietic tissue, and by examining the in vivo responses o f reconstituted mice to pig skin grafts, Neonatal tissue was studied b ecause it might be more practicable than fetal tissue for the purpose of transplantation to primates. BALB/c nu/nu mice transplanted with ne onatal (<24-hr-old) pig thymus and spleen fragments developed circulat ing mouse CD4(+) cells. The pig thymus grafts were necessary for mouse T-cell development, as CD4 recovery did not occur in recipients of ne onatal pig splenic tissue alone, The CD4(+) cells that developed inclu ded V beta 8.1/2(+) T cells in similar proportions as in BALB/c mice, and V beta 11(+) and V beta 5(+) CD4 T cells were deleted almost as co mpletely as in normal BALB/c mice, This deletion was detected among CD 4 single-positive graft thymocytes. In 9 of 12 evaluable animals, mixe d lymphocyte responses demonstrated tolerance to donor type pig SLA an tigens, with responsiveness to alloantigens and/or third-party pig xen oantigens. Furthermore, grafting of neonatal pig thymus conferred the ability to reject allogeneic mouse skin in 7 of 10 animals, In additio n, 7 of 10 animals accepted paternal (donor SLA-matched) skin (median survival time [MST] > 100 days), whereas 4 of 4 animals rejected third -party SLA-mismatched pig skin (MST=40.5 days). We conclude that neona tal pig thymi transplanted to BALB/c nu/nu mice can support the develo pment of mouse CD4(+) cells that are functional and specifically toler ant to donor-type pig antigens.