A serine protease inhibitor, N-alpha-tosyl-l-lysine chloromethyl ketone, prolongs rat hepatic allograft survival.
BACKGROUND
Serine protease inhibitors have profound suppressive effects on cellular and humoral immune responses. We investigated the effect of a serine protease inhibitor, N-alpha-tosyl-l-lysine chloromethyl ketone (TLCK), on hepatic allograft survival in rats. Methods. Orthotopic hepatic transplantation was performed in an ACI (RT1(a))-to-LEW (RT1(1)) rat combination. TLCK was administered continuously at a dose of 4.4 mg/kg/day using an osmotic subcutaneous infusion minipump.


RESULTS
TLCK prolonged hepatic allograft survival. Histologic staging of acute rejection based on Banff criteria in TLCK-treated hepatic allografts was significantly lower than in untreated allografts. TLCK significantly reduced serum concentrations of interferon (IFN)-gamma and tumor necrosis factor (TNF) alpha in allograft recipients. TNF-alpha mRNA levels in TLCK-treated allografts were significantly lower than in untreated allografts. TLCK also decreased perforin mRNA levels in hepatic allografts. Hepatic infiltrates eluted from TLCK-treated allografts showed significantly lower cell-mediated lympholytic activity against donor Con A blast cervical lymph node cells than those from untreated allografts. In vitro, TLCK suppressed interleukin-2 production and [(3)H]thymidine incorporation into an allogeneic mixed lymphocyte reaction.


CONCLUSIONS
TLCK suppressed acute allograft rejection, suggesting a novel immunosuppressive strategy for therapy of acute organ rejection.
Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan.
J L
JL
Zhang
Y
Y
Yamaguchi
K
K
Mori
K
K
Okabe
H
H
Hidaka
H
H
Ohshiro
S
S
Uchino
K
K
Ishihara
T
T
Furuhashi
S
S
Yamada
M
M
Ogawa
D000818:Animals; D006084:Graft Rejection / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects*; D007165:Immunosuppression Therapy / Q000379:methods; D007260:Infusion Pumps; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D014107:Tosyllysine Chloromethyl Ketone / Q000008:administration & dosage / Q000494:pharmacology*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics
D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014107:Tosyllysine Chloromethyl Ketone; D007371:Interferon-gamma