title: Induction and maintenance of T-dependent or T-independent xenotolerance by nonprimarily-vascularized skin or thymus grafts.
abstract: BACKGROUND
  The success of clinical xenotransplantation will depend on induction of xenotolerance. We have previously shown that combined xenothymus and vascularized xenoheart transplantation under the coverage of a tolerizing regimen (TR) can induce and maintain full xenotolerance. Here, induction/maintenance of xenotolerance using nonprimarily-vascularized thymus and/or skin grafts was investigated.
  
  
  METHODS
  Hamster skin or thymus or combined skin and thymus transplantation was performed in nude rat recipients with or without administering a TR (NK cell depletion, day -14; xenoantigen infusion, day -14; Leflunomide, day -14 through +14). Xenotolerance was confirmed by subsequent transplantation of a vascularized hamster heart, measurement of xenoantibody formation, or mixed lymphocyte reaction (MLR).
  
  
  RESULTS
  Skin grafts were as effective as vascularized heart grafts to induce/maintain T-independent xenotolerance. Even without TR and despite being rejected themselves, xenoskin grafts lead to progressively developing xenononreactivity. Xenothymus transplantation induced xenotolerance in the T-dependent but not in the T-independent immune compartment, leading to rejection of subsequently transplanted hamster hearts by T-independent mechanisms (production of IgM but not IgG xenoantibodies (Xabs), presence of antihamster MLR nonresponsiveness). Combined skin and thymus xenotransplantation sensitized the T-cell compartment, leading to hyperacute rejection of subsequently transplanted hamster hearts. This was not the case when the skin grafts were transplanted late (2 months) after the thymus grafts.
  
  
  CONCLUSIONS
  Xenogeneic skin and xenogeneic thymus grafts have opposite xenotolerance inducing capacities in the T-independent as compared to the T-dependent immune compartment. Thymus grafts induce and maintain T-dependent but not T-independent xenotolerance. Skin grafts alone induce T-independent xenotolerance but sensitize the T-cell compartment when transplanted concomitantly with thymus grafts.
authors.affiliation: Laboratory for Experimental Transplantation, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Lisong
authors.initials: L
authors.lastname: Yu
authors.forename: Yehong
authors.initials: Y
authors.lastname: Yan
authors.forename: Shengqiao
authors.initials: S
authors.lastname: Li
authors.forename: Omer
authors.initials: O
authors.lastname: Rutgeerts
authors.forename: Jozef
authors.initials: J
authors.lastname: Goebels
authors.forename: Constant
authors.initials: C
authors.lastname: Segers
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.forename: Michel
authors.initials: M
authors.lastname: Vandeputte
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
mesh_terms: D000818:Animals; D000910:Antibodies, Heterophile / Q000096:biosynthesis; D006224:Cricetinae; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008647:Mesocricetus; D051381:Rats; D012867:Skin / Q000098:blood supply; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000637:transplantation*; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D000910:Antibodies, Heterophile