title: Vascularized thymic lobe transplantation in a pig-to-baboon model: a novel strategy for xenogeneic tolerance induction and T-cell reconstitution.
abstract: 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.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Shin
authors.initials: S
authors.lastname: Yamamoto
authors.forename: John M
authors.initials: JM
authors.lastname: Lavelle
authors.forename: Parsia A
authors.initials: PA
authors.lastname: Vagefi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Arakawa
authors.forename: Emma
authors.initials: E
authors.lastname: Samelson-Jones
authors.forename: Shannon
authors.initials: S
authors.lastname: Moran
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Teranishi
authors.forename: Chisako
authors.initials: C
authors.lastname: Kamano
authors.forename: Jay
authors.initials: J
authors.lastname: Fishman
authors.forename: Michel
authors.initials: M
authors.lastname: Awwad
authors.forename: David M
authors.initials: DM
authors.lastname: Neville
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents