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.