Late CD8+ T cell-dependent xenoantibody production in innate tolerant nude rats after hamster islet grafting but not after hamster heart grafting.
BACKGROUND
Xenograft rejection can be provoked by both the innate and adaptive immune compartments and close reciprocal interactions exist between these two systems. We investigated the interdependent roles of T and B lymphocytes in vascularized (heart) and cellular (islet) xenograft rejection in a model with established xeno-nonreactivity of the innate immune system.


METHODS
Specific innate xenotolerance was induced in nude rats bearing either a hamster heart or a hamster pancreatic islet graft by a tolerizing regimen consisting of donor antigen infusion, temporary natural killer cell depletion and a 4-week administration of leflunomide. One month after transplantation, syngeneic CD4 and CD8 T cells were adoptively transferred.


RESULTS
Both vascular and cellular xenografts were rejected after CD4 T cell reconstitution, corresponding with production of high IgM and IgG xenoantibody titers. Deposition of xenoantibodies and complement was seen in the heart but not in the islet xenografts. After infusion of CD8 T cells, xenohearts underwent a delayed type of rejection without xenoantibody production and xenoislets were not rejected. In xenoislet recipients, CD8 dependent B cells were not tolerized, resulting in the production of IgG xenoantibodies belonging to Th2-dependent isotypes, known not to cause graft rejection, and deposited at the graft implantation site.


CONCLUSIONS
We conclude that distinct mechanisms of immune activation underlie xenogeneic reactions against vascular and cellular grafts.
Devos
Timothy
T
Department of Experimental Medicine, Laboratory for Experimental Transplantation, University of Leuven, Leuven, Belgium.
Shengqiao
Li
L
Gysemans
Conny
C
Yan
Yehong
Y
Damme
Boudewijn Van
BV
Nelson-Holte
Molly
M
Billiau
An D
AD
Waer
Mark
M
Mathieu
Chantal
C
D000818:Animals; D000910:Antibodies, Heterophile / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006224:Cricetinae; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D009928:Organ Specificity; D051381:Rats; D011923:Rats, Nude; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*
D000910:Antibodies, Heterophile