Prolonged discordant xenograft survival and delayed xenograft rejection in a pig-to-baboon orthotopic cardiac xenograft model.
OBJECTIVE
Our objectives were to study delayed xenograft rejection and the effectiveness of pretransplantation total lymphoid irradiation combined with immunosuppression on rejection in a pig-to-baboon cardiac xenograft model.


METHODS
Baboons were treated with pretransplantation total lymphoid irradiation, cyclosporine A (INN: ciclosporin), and methotrexate. Orthotopic pig-to-baboon cardiac transplantations were performed after depletion of circulating xenoreactive natural antibody by pretransplantation donor organ hemoperfusion. Tissue samples were collected for immunologic and immunopathologic evaluation.


RESULTS
Pig cardiac xenografts survived more than 18 and 19 days without evidence of hyperacute rejection. Immunologic analysis of serum samples demonstrated that circulating xenoreactive natural antibody levels did not return to pretransplantation levels. The production of xenoreactive natural antibodies from the recipient's splenocytes was inhibited completely. Histologic examination of xenografts showed the feature of acute vascular rejection. Immunohistochemical studies demonstrated infiltration of cardiac xenografts by large numbers of macrophages, small numbers of natural killer cells, and a few T cells. The infiltrating macrophages also showed expression of interleukin-1 and tumor necrosis factor. Diffuse deposition of immunoglobulin G, C1Q, C3, and fibrin on xenograft vasculature was observed. Interleukin-2 expression was not found in rejected cardiac xenografts. Xenograft endothelial cells also showed evidence of activation (expression of cytokines interleukin-1 and tumor necrosis factor).


CONCLUSIONS
This study demonstrates prolonged discordant cardiac xenograft survival and delayed xenograft rejection in a pig-to-baboon model. The delayed xenograft rejection is mediated by both humoral and cellular mechanisms. Pretransplantation total lymphoid irradiation combined with cyclosporine A and methotrexate can inhibit xenoreactive natural antibody production but not elicited antipig antibody production and the xenoreactivity of macrophages.
Xu
H
H
Department of Surgery, Loma Linda University Medical Center, Calif 92354, USA.
Gundry
S R
SR
Hancock
W W
WW
Matsumiya
G
G
Zuppan
C W
CW
Morimoto
T
T
Slater
J
J
Bailey
L L
LL
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007136:Immunoglobulins / Q000032:analysis; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000473:pathology; D015182:Lymphatic Irradiation; D008264:Macrophages / Q000473:pathology; D008727:Methotrexate / Q000627:therapeutic use; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D010215:Papio; D013552:Swine; D013601:T-Lymphocytes / Q000473:pathology; D014183:Transplantation, Heterologous
D016207:Cytokines; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D008727:Methotrexate