Cyclophosphamide-induced tolerance in rat orthotopic liver transplantation.
BACKGROUND
We previously established a cyclophosphamide (CP)-induced tolerance system in rodent skin graft models. In this study, we applied this system to rat liver transplantation.


METHODS
Lewis recipients were inoculated on day -2 with spleen and bone marrow cells (SC+BMC) from Dark Agouti (DA) donors, followed by 100 mg/kg CP on day 0. On day 25, DA livers were orthotopically grafted. We assessed the alloresponses to the donors of the long-term surviving recipients, using the second skin grafting and in vitro assay.


RESULTS
The recipients that had been treated with SC+BMC and CP survived for more than 165 days. None of control group that received SC+BMC alone (mean survival times [MST]=13.8 days), CP alone (MST=40.0), SC+BMC from third-party PVG rats and CP (MST=45.0), or no treatment (MST=13.8) survived over 50 days. The donor-specific tolerance was confirmed by second skin grafts onto recipients with permanent DA liver grafts, which accepted DA skins (MST>75) but not PVG (MST=8.3). However, the lymphocytes from the tolerant recipients showed alloresponse to DA in vitro. To investigate whether the T helper type 2 deviation contributed to this "split tolerance," we assessed the production of cytokines in mixed lymphocyte reaction. Interleukin 2 and interferon-gamma were detected but interleukin 4 was not.


CONCLUSIONS
These data showed that this protocol induced split tolerance in rat liver transplantation and, furthermore, the mechanism of split tolerance was not due to T helper 2 deviation.
Okano
S
S
Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Japan. okano@hofu-icho.or.jp
Eto
M
M
Tomita
Y
Y
Yoshizumi
T
T
Yamada
H
H
Minagawa
R
R
Nomoto
K
K
Sugimachi
K
K
Nomoto
K
K
D000818:Animals; D001663:Bilirubin / Q000097:blood; D003520:Cyclophosphamide / Q000494:pharmacology*; D006085:Graft Survival; D007108:Immune Tolerance / Q000187:drug effects*; D016031:Liver Transplantation / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D016038:Skin Transplantation; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D013997:Time Factors; D018183:Transplantation Chimera
D003520:Cyclophosphamide; D001663:Bilirubin