The salutary effect of FK506 in ischemia-reperfusion injury of the canine liver.

The present study was designed to elucidate the effect of FK506 on 90 min of warm ischemia of the liver and reperfusion in 30 dogs. Three groups of animals were studied. Group 1 animals received FK (0.15 mg/kg/day) for three days prior to the ischemia and group 2 animals got 2 ml of saline solution for three days instead of FK and were considered controls. In group 3 FK (0.15 mg/kg/day) was injected immediately upon reperfusion and two days thereafter. Evaluation of the effectiveness of the drug was monitored by measuring the serum activities of AST, ALT, LDH, serum total bilirubin, malondialdehyde, and by histopathological examinations of the liver specimens and survival of the animals for 7 days after reperfusion. The 7 day survival of the animals in group 1 (80%) was significantly (P < 0.05) improved compared with those in group 2 (30%) and group 3 (20%). The serum activities of AST, ALT, and LDH and total bilirubin were significantly lower in group 1 than in group 2 and group 3. FK pretreatment significantly prevented hepatocellular necrosis and neutrophilic infiltration in group 1 in comparison with those in group 2 and group 3. Although the malondialdehyde level in hepatic venous blood was relatively lower in group 1, this difference was not statistically significant. Three days FK pretreatment prevented hepatocellular injury and enzyme leakage after 90 min of hepatic ischemia, whereas FK treatment immediately upon reperfusion failed to do so. In conclusion, donor organ pretreatment with FK may become a promising strategy for improved allograft survival in liver transplantation.     

CD152 and PD-1 Down-Regulation on CD8 T Cells Is Associated With Human Acute Liver Allograft Rejection

PurposeTo investigate CD152 and PD-1 expression on T lymphocytes and the function of CD152- and PD-1–positive CD8 T cells in human acute liver allograft rejection.Materials and methodsSixty-three patients undergoing liver transplantation were enrolled in this study, including 26 cases with acute allograft rejection (Gr-AR) and 37 cases with stable allograft liver function (Gr-SF). The expression of CD152 and PD-1 on T lymphocytes and the expression of granzyme and perforin on CD152- and PD-1–positive CD8 T cells in peripheral blood were analyzed using flow cytometry.ResultsThe peripheral CD4/CD8 ratio in Gr-AR was significantly lower than that in Gr-SF (P < .01). The expression of CD152 and PD-1 on CD8 and CD4 T cells was significantly lower in Gr-AR than in Gr-SF (all P < .01). The expression of granzyme B and perforin was significantly higher in Gr-AR than in Gr-SF (P < .01).ConclusionsDown-regulation of the expression of negative costimulatory molecules such as CD152 and PD-1 on CD8 T cells may be associated with human acute liver allograft rejection.     

FK506对离体肝再灌注后TNF-α mRNA表达的影响

目的探讨 FK506 对肝脏保存再灌注中TNF-α mRNA表达的影响 .方法建立离体大鼠肝脏再灌注模型,应用RT-PCR方法检测TNF-α mRNA的表达,观察FK506对不同时间保存的肝脏TNF-α mRNA表达的影响. 结果 FK506组保存16,24和32h 再灌注,TNF-α mRNA表达分别为0.83±0.07,0.91±0.06和1.32±0.08, 明显低于对照组的0.98±0.05,1.42±0.09和1.86±0.16. 结论 FK506能抑制肝脏保存再灌注中TNF-α mRNA的表达,对离体肝的再灌注损伤可能具有保护作用.     

FK 506 inhibits tolerance induction in mice liver transplantation

BACKGROUND: In the orthotopic mouse liver transplantation model, allografts are accepted without immunosuppression, and donor-specific tolerance is induced upto 40 days. Although FK 506 is a well-known immunosuppressive agent, its influence on tolerance induction is not known. In this study, we examined the influence of FK 506 on tolerance induction in a mouse liver transplant model. METHODS: Orthotopic liver transplantation was performed from B10.BR (H-2K) to B10.D2 (H-2D mice). In the experimental group, FK 506 (1 mg/kg/d) was given subcutaneously to the recipients from day 0 to day 21, whereas the control group received a placebo (1 mg/kg/d). On day 40, donor skin grafts were transplanted to the recipients to examine the survival times of the recipients and the skin grafts. On day 14, donor-type cells in recipient's blood, spleen, kidney, thymus, and lymph nodes were examined by RT-PCR using specific donor-type MHC class I and II primers. RESULTS: All recipients survived for more than 100 days. The mean survival time of skin grafts in the experimental group was significantly reduced compared to that of controls. On day 14, either donor-type MHC class I- or class II-positive cells were detected in the control group, whereas donor-derived MHC class II-positive cells disappeared in the experimental group. CONCLUSIONS: In the early period after mouse liver transplantation, FK 506 inhibits tolerance induction paradoxically. Some donor-derived MHC class II-positive cells might play an important role in tolerance induction.     

FK506 conversion for intractable rejection of the liver allograft

Twenty-seven liver transplant recipients with intractable, biopsy-proven, acute or chronic rejection (defined as vanishing bile duct syndrome) were conerted from cyclosporin to FK506. Successful conversion was achieved in 9 of 15 patients with acute rejection and in 6 of 12 patients with vanishing bile duct syndrome. A normal bilirubin was achieved more quickly in those with acute rejection (within 1 moth) than in those with chronic rejection (within 3 months). A preconversion total bilirubin of less than 12 mg/dl was considered significant with regard to a successful outcome (P=0.002). Graft survival was 66.7% and patient survival 73% in the case of acute rejection, and 50% and 66.7%, respectively, in the case of chronic rejection. Nephrotoxicity, neurotoxicity, and gastroitestinal side effects were the most serious complications of FK506 conversion. Six of ten patients had a drop in GFR that was 50% or greater a minimum of 1 month of FK506 exposure. The mean maintenance dose of FK506 to maintain FK506 serum levels of 0.5–1.5 ng/ml was 0.07 mg/kg per 12 h for adults (half the recommended dose), compared to 0.15 mg/kg per 12 h for pediatric patients. This study demonstrates that FK506 can be used successfully to convert patients with intractable acute and chronic rejection. Careful adjustments of FK506 dosages and levels are required to minimize side effects.     

Long-term use of FK 506 in living related liver transplantation

Abstract FK 506 (Tacrolimus) was used with steroids to treat 61 pediatric patients who received living related partial liver transplantation. Fifty-two recipients survived and 9 died between 6 months and 3 years after transplantation. In the surviving patients, oral doses of Tacrolimus were tapered from 0.298 ± 0.277 mg/kg daily at 1 month after transplantation to 0.078 ± 0.054 at 24 months after transplantation. The 12 h trough levels of Tacrolimus were 12.6 ± 7.1 ng/ml and 4.1 ± 2.4 at 1 and 24 months after transplantation, respectively. The percentage of recipients free from steroids was 77%, 97%, and 94% at 6, 12, and 24 months after transplantation, respectively. Liver allograft rejection was encountered in seven recipients, five of whom were treated by steroid pulse therapy and a dose increase of Tacrolimus; the remaining two required OKT3. However, there was no episode of rejection that required retransplantation. Infectious complications encountered in 34 patients included 12 bacterial, 3 fungal, and 19 viral infections. Two recipients died one of fungal pneumonia and one of Epstein-Barr virus-associated lymphoproliferative disorder. Regarding adverse reactions of Tacrolimus, hypertension was observed in 28 patients, diabetes mellitus in 3, pancreatitis in 3, convulsion in 1, tremor in 12, itching in 5, and pigmentation in the oral mucosa in 2. Slightly increased values of creatinine were observed in most of the patients; however, an abnormal increase of serum of serum creatinine (> 1.0 mg/dl) was confined to the complicated cases. Improvement of somatic growth was observed in 21 patients (62%) and 13 (75%) at 12 and 24 months after transplantation, respectively. The long-term use of Tacrolimus is highly effective in terms of its immunosuppressive potential and reduced adverse reaction. Steady growth development can be expected in pediatric recipients free from steroids.     

The effect of FK506 treatment on pancreaticoduodenal allotransplantation in the primate.

The effect of FK506 monotherapy on pancreaticoduodenal allotransplantation was studied in a primate model. The recipients were made diabetic by total pancreatectomy, thus glycemic control depended on the graft. In control animals hyperglycemia occurred after 14 +/- 3 days and the animals died after 36 +/- 15 days. For FK506-treated animals, the time until development of hyperglycemia was 60 +/- 12 days (P less than 0.05). The animals were then sacrificed by day 90 (P less than 0.05). All three control animals lost their graft function because of severe rejection, as verified by postmortem examination. Only one of the five treated animals showed evidence of a moderate-to-severe rejection at 90 days, one animal having a mild rejection as judged by the histological findings. The drug was clinically well tolerated in all except one animal that became apathetic and refused to eat. Hyperglycemia and an elevated serum creatinine level, which were probably related to the FK506 treatment, occurred in one animal each. Both of these side-effects were reversed by reducing the dose. Thus the use of FK506 permits successful single pancreatic transplantation in primates.