Cardiac allograft survival across major histocompatibility complex barriers in the rhesus monkey following T lymphocyte-depleted autologous marrow transplantation. II. Prolonged allograft survival with extensive marrow T cell depletion.
In the present study, we tested the possibility that a vascularized allograft might induce immunological tolerance in a myeloablated host, similar to the tolerance induced by allogeneic bone marrow grafts. To this end, we developed a rhesus monkey model consisting of myeloablative total-body irradiation and T cell-depleted autologous marrow transplantation followed by MHC-mismatched heterotopic cardiac allograft implantation. Limiting dilution analysis was used to quantify residual marrow T cells following depletion. We found that (1) allograft survival was substantially prolonged in the absence of immunosuppressive drugs (median survival = 160 days) over that seen in controls treated identically but receiving non-T cell-depleted marrow (median survival = 14 days); (2) there was a correlation between allograft survival prolongation and the extent of marrow T cell depletion, with a maximum survival of 329 days associated with a residual marrow T cell content of 0.00014%; (3) nonspecific immune deficiency--and, possibly, specific unresponsiveness of limited duration (determined by cryopreserved donor and third-party skin grafting)--contributed to the rejection-free period seen in recipients of extensively depleted marrow; (4) late allograft rejection occurred in 3 of 3 long-term survivors, thereby demonstrating that permanent tolerance was not induced by the allograft across MHC barriers; and (5) as few as 1.4 x 10(4) infused marrow T cells/kg were sufficient to mediate acute allograft rejection, a threshold approximately 10-fold lower than that reported for the induction of acute graft-versus-host disease following allogeneic bone marrow transplantation.
Moses
R D
RD
Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892.
Orr
K S
KS
Bacher
J D
JD
Sachs
D H
DH
Clark
R E
RE
Gress
R E
RE
D000818:Animals; D016026:Bone Marrow Transplantation; D005260:Female; D006085:Graft Survival; D016027:Heart Transplantation; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D008285:Major Histocompatibility Complex; D008297:Male; D016038:Skin Transplantation; D013601:T-Lymphocytes; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation