Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys.
BACKGROUND
We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after nonmyeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients.


METHODS
Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week posttransplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0.


RESULTS
Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODs] 43 and 56). Three monkeys developed multilineage chimerism, which persisted 20 to 43 days posttransplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hyporesponsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3% to 9.5% of donor coronary arteries exhibited intimal proliferation.


CONCLUSIONS
The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts.
Kawai
Tatsuo
T
Transplantation Unit, Division of Cardiac Surgery, Massachusetts General Hospital, White 510, 55 Fruit Street, Boston, MA 02114, USA.
Cosimi
A Benedict
AB
Wee
Siew Lin
SL
Houser
Stuart
S
Andrews
David
D
Sogawa
Hiroshi
H
Phelan
Joanne
J
Boskovic
Svetlan
S
Nadazdin
Ognjenka
O
Abrahamian
Gregory
G
Colvin
Robert B
RB
Sach
David H
DH
Madsen
Joren C
JC
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning