Induction and maintenance of T-dependent or T-independent xenotolerance by nonprimarily-vascularized skin or thymus grafts.
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.
Yu
Lisong
L
Laboratory for Experimental Transplantation, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
Yan
Yehong
Y
Li
Shengqiao
S
Rutgeerts
Omer
O
Goebels
Jozef
J
Segers
Constant
C
Lin
Yuan
Y
Vandeputte
Michel
M
Waer
Mark
M
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*
D000910:Antibodies, Heterophile