Liver allografts are toleragenic in rats conditioned with posttransplant total lymphoid irradiation.
BACKGROUND
Posttransplant total lymphoid irradiation (TLI) treatment has been applied to tolerance induction protocols in heart and kidney transplantation models.


METHODS
We examined the efficacy and mechanism of posttransplant TLI treatment in the induction and maintenance of tolerance in a rat orthotopic liver transplantation model.


RESULTS
Posttransplant TLI prolonged ACI (RT1(a)) liver allograft survival in Lewis (RT1(b)) hosts, with 50% long-term engraftment without immunosuppression and without evidence of chronic rejection. Injection of donor-type liver mononuclear cells (LMCs) facilitated the prolongation of graft survival, with more than 70% of grafts in LMC recipients surviving more than 100 days without chronic rejection. Recipients with long-term liver allograft survival accepted ACI but not PVG skin grafts. In TLI-conditioned recipients with accepted grafts, apoptosis occurred predominantly in graft-infiltrating leukocytes. In contrast, there were few apoptotic leukocytes in rejecting grafts. Recipients with long-term graft acceptance (>100 days of survival) demonstrated evidence of immune deviation; mixed lymphocyte reaction to ACI stimulator cells was vigorous, but secretion of interferon-gamma and interleukin-2 was reduced. In tolerant recipients, the number of Foxp3(+) CD25(+) CD4(+) regulatory T cells was increased in the liver allograft as well as in the peripheral blood.


CONCLUSIONS
We conclude that posttransplant TLI induces tolerance to liver allografts via a mechanism involving apoptotic cell-deletion and immunoregulation.
Nagasaki
Kazuhito
K
Department of Surgery, Division of Transplantation, Stanford University School of Medicine, Stanford, CA, USA.
Obara
Hideaki
H
Xiong
Anming
A
Kambham
Neeraja
N
Strober
Samuel
S
Esquivel
Carlos O
CO
Millan
Maria T
MT
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000378:metabolism; D046528:Chimerism; D051858:Forkhead Transcription Factors / Q000235:genetics; D006085:Graft Survival / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016031:Liver Transplantation / Q000276:immunology*; D015182:Lymphatic Irradiation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051381:Rats; D016038:Skin Transplantation / Q000276:immunology; D015996:Survival Rate; D013997:Time Factors; D014158:Transcription, Genetic / Q000235:genetics; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D015854:Up-Regulation
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma