Vascularized thymic lobe transplantation in a pig-to-baboon model: a novel strategy for xenogeneic tolerance induction and T-cell reconstitution.
BACKGROUND
This laboratory has previously demonstrated the induction of allogeneic tolerance by vascularized thymic lobe (VTL) transplantation in miniature swine. We report here our initial attempt to induce tolerance by VTL transplantation in the clinically relevant, discordant, pig-to-baboon model of xenotransplantation.


METHODS
Six baboons received xenografts of hDAF VTLs. Four of these baboons also received omental thymic tissue implants. All recipients were treated with an immunosuppressive conditioning regimen that included thymectomy, splenectomy, extracorporeal immunoadsorption of anti-alpha Gal antibodies, and T-cell depletion. Two control baboons received sham operations, of which one also received 5x10 hDAF porcine thymocytes/kg intravenously.


RESULTS
Transplanted VTL grafts supported early thymopoiesis of recipient-type immature thymocytes, and facilitated engraftment of nonvascularized thymic omental implants. Recipients of the VTL grafts demonstrated donor-specific unresponsiveness in MLR assays, development of peripheral CD45RAhigh/CD4 double positive (DP) cells, and positive cytokeratin staining of thymic stroma in the grafts for 2 months following xenotransplantation. The control baboons did not show these markers of thymic reconstitution. The eventual return of Gal natural antibodies led to the destruction of graft epithelial cells and the rejection of all VTL grafts by 3 months posttransplantation.


CONCLUSIONS
VTL transplantation from hDAF swine to baboons induced early thymopoiesis in the recipients and donor-specific cellular unresponsiveness in vitro. When coupled with additional strategies aimed at silencing humoral rejection, VTL transplantation may significantly prolong xenograft survival and result in long-term tolerance.
Yamamoto
Shin
S
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
Lavelle
John M
JM
Vagefi
Parsia A
PA
Arakawa
Hitoshi
H
Samelson-Jones
Emma
E
Moran
Shannon
S
Teranishi
Katsuhito
K
Kamano
Chisako
C
Fishman
Jay
J
Awwad
Michel
M
Neville
David M
DM
Shimizu
Akira
A
Sykes
Megan
M
Sachs
David H
DH
Yamada
Kazuhiko
K
D000818:Animals; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D017710:Lymphocyte Transfusion; D008297:Male; D023421:Models, Animal; D010215:Papio; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000098:blood supply* / Q000637:transplantation*; D023001:Transplantation Tolerance; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000379:methods
D007166:Immunosuppressive Agents