Improvement in rejection of human decay accelerating factor transgenic pig-to-primate renal xenografts with administration of rabbit antithymocyte serum.
BACKGROUND
Survival in pig-to-baboon kidney xenotransplantation is currently limited by acute humoral xenograft rejection (AHXR). We hypothesized that the administration of rabbit antithymocyte serum (RATS) would delay or prevent AHXR as compared with a cyclophosphamide (CyP)-based immunosuppressive regimen.


METHODS
Nine baboons received life-supporting heterotopic single-kidney transplants from human decay accelerating factor transgenic pigs. Immunosuppression consisted of GAS (a galactosyl alpha-1,3-galactose analog), cyclosporine, and steroids. Group 1 (n=2) was also treated with CyP and a rapamycin derivative (RAD), group 2 (n=4) received RATS and RAD, and group 3 (n=3) received only RATS. Animals were maintained until death or sacrifice because of uncontrollable rejection or other complications. Graft histopathology was assessed at the study endpoint.


RESULTS
Mean survival was 28+/-11.3 days, 23+/-2.5 days, and 20+/-2.5 days for groups 1, 2, and 3 (not significant). Graft rejection was the cause of death in both CyP-treated animals. One RATS-treated animal died of rejection; the others died of infections or bleeding. Two RATS-treated animals developed posttransplant lymphoproliferative disorder, and one died of cytomegalovirus pneumonitis. Histopathology revealed severe AHXR in group 1 kidneys, involving 100+/-0% of the tissue examined. In contrast, AHXR was reduced in groups 2 and 3, involving 21+/-14% and 18+/-28%, respectively, of the tissue examined (P<0.01).


CONCLUSIONS
Substitution of RATS for CyP was well tolerated and resulted in reduced severity of AHXR in this model. Complications seen in RATS-treated animals may be preventable through the use of standard prophylaxis for infections. Our data suggest that further studies are warranted to explore the use of antilymphocyte agents in xenotransplantation.
Department of Surgery, University of Toronto, Toronto General Hospital, Ontario, Canada.
Anand
A
Ghanekar
Ginette
G
Lajoie
Yigang
Y
Luo
Hongji
H
Yang
Jinsub
J
Choi
Bertha
B
Garcia
Edward H
EH
Cole
Paul D
PD
Greig
Mark S
MS
Cattral
M James
MJ
Phillips
Carl J
CJ
Cardella
Gary A
GA
Levy
Robert
R
Zhong
David R
DR
Grant
D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000097:blood; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D018958:CD55 Antigens / Q000235:genetics*; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D016030:Kidney Transplantation; D008297:Male; D008854:Microscopy, Electron; D023421:Models, Animal; D009336:Necrosis; D010215:Papio; D011817:Rabbits; D013552:Swine; D014183:Transplantation, Heterologous
D000910:Antibodies, Heterophile; D000961:Antilymphocyte Serum; D018958:CD55 Antigens