Heart xenograft survival with chimeric pig donors and modest immune suppression.
OBJECTIVE
To assess the use of donor pigs with cellular chimerism for prevention of acute rejection with modest immune suppression. The clinical use of pig organ xenografts is currently precluded by severe acute rejection, which resists standard immune suppression.


BACKGROUND
For long-term survival of pig organ xenografts, immune suppression significantly greater than used with allografts would currently be necessary, leaving the recipient immune deficient and at increased risk for infections. Induction of immune tolerance and tissue accommodation could enhance xenograft survival but would lead to complications and frequent graft failure. Induction of cellular chimerism within the donor pigs, however, could accomplish these goals before transplantation, significantly reducing the risk.


METHODS
Marrow cells from sheep were infused into fetal pigs. Heart xenografts from chimeric or nonchimeric pigs were transplanted heterotopically into recipient sheep, simultaneous with infusion of splenocytes. Posttransplant suppression consisted of cyclosporine and tapered corticosteroids, comparable with allotransplants.


RESULTS
All of the control grafts (n = 12) were rejected by acute vascular rejection in 4 to 8 days. In contrast, only one episode of vascular rejection was observed in the experimental group (n = 13). Four experimental recipients had an episode of moderate diffuse cellular rejection (grade 3) and one had moderate focal cellular rejection (grade 2). Each episode responded to pulse steroids. Seven grafts showed no significant rejection. There was little evidence of immune deficiency, infection, or toxicity.


CONCLUSIONS
Acute vascular rejection was prevented in a large animal model without the need for severe immune suppression.
Beschorner
William E
WE
Department of Surgery, Transplantation Section, University Nebraska Medical Center, Omaha, NE 68198-3285, USA. beschorner@ximerex.com
Sudan
Debra L
DL
Radio
Stanley J
SJ
Yang
Tianyu
T
Franco
Kenneth L
KL
Hill
Arthur C
AC
Shearon
C Carson
CC
Thompson
Scott C
SC
Dixon
Robert S
RS
Johnson
Noel D
ND
Kuszynski
Charles A
CA
Rubocki
Ronald J
RJ
Lechtenberg
Kelly F
KF
Matamoros
Aurelio
A
Goertzen
Timothy C
TC
Fox
Ira J
IJ
Langnas
Alan N
AN
D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D016572:Cyclosporine / Q000627:therapeutic use; D016332:Fetal Tissue Transplantation / Q000276:immunology* / Q000379:methods; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control; D006321:Heart / Q000196:embryology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007153:Immunologic Deficiency Syndromes / Q000209:etiology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D008776:Methylprednisolone Hemisuccinate / Q000627:therapeutic use; D023421:Models, Animal; D012756:Sheep; D013552:Swine; D018183:Transplantation Chimera / Q000235:genetics* / Q000276:immunology*; D023001:Transplantation Tolerance / Q000235:genetics* / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*; D016042:Transplantation, Heterotopic
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D008776:Methylprednisolone Hemisuccinate; D016572:Cyclosporine