Survival of accommodated cardiac xenografts upon retransplantation into cyclosporine-treated recipients.
BACKGROUND
Accommodation designates the survival of vascularized grafts in the presence of circulating antigraft antibodies and complement. In the hamster-to-rat model, accommodation is associated with an ongoing T helper (Th)2 cytokine response and the expression of "protective genes" by the graft endothelial cells and smooth muscle cells. In this report, we tested whether accommodated xenografts would be protected from rejection upon retransplantation into second recipients treated with cyclosporine (CsA), a treatment that does not prolong survival of a fresh hamster heart.


METHODS
Long-term survival of hamster-to-rat cardiac xenografts was achieved using either CsA plus cobra venom factor (CVF) or CsA plus rapamycin. Xenografts that survived long term in their first recipients were retransplanted into second recipients treated with CsA.


RESULTS
Long-term xenograft survival in CsA/CVF-treated recipients was associated with an ongoing Th2 response, expression of protective genes, and deposition of elicited xenoreactive antibodies and complement on the graft endothelium. In CsA/rapamycin-treated recipients, long-term xenograft survival occurred in the presence of basal levels of antigraft antibodies and was not associated with a Th2 cytokine response or the expression of protective genes. Xenografts from CsA/CVF-treated rats survived significantly longer upon retransplantation into second recipients treated with CsA (77.3% >10 days) as compared with xenografts from CsA/rapamycin-treated rats (4-11 days) or naive hearts (3-4 days). Moreover, 30-35% of xenografts from CsA/CVF rats survived long term and accommodated in the second recipient.


CONCLUSIONS
Accommodated xenografts can have significantly prolonged acceptance when retransplanted into second recipients treated with CsA alone; in contrast, naive hearts or hearts that survived long term in first recipients, but did not accommodate, did not survive long term in the second recipients. We suggest that prolonged survival of accommodated xenografts is due to the expression of the protective genes A20, bcl-2 bcl-xL, and heme oxygenase-1 in the xenograft endothelium and possibly smooth muscle cells.
Miyatake
T
T
Center for Immunobiology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Koyamada
N
N
Hancock
W W
WW
Soares
M P
MP
Bach
F H
FH
D000818:Animals; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology*; D004546:Elapid Venoms / Q000494:pharmacology; D006085:Graft Survival; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D011090:Polyenes / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D012086:Reoperation; D020123:Sirolimus; D014183:Transplantation, Heterologous
D004546:Elapid Venoms; D007166:Immunosuppressive Agents; D011090:Polyenes; C016310:cobra venom factor; D016572:Cyclosporine; D020123:Sirolimus