HBsAg-树突状细胞疫苗对肝移植后免疫抑制状态大鼠抗-HBs产生的影响

目的 观察乙型肝炎表面抗原(HBsAg)冲击的树突状细胞(DCs)疫苗对肝移植(LT)术后处于免疫抑制状态大鼠的抗一HBs产生的影响.方法 Lewis大鼠LT术后(BN大鼠为供体)给予大剂量他克莫司(FK506,2 mg/kg),建立LT术后免疫抑制状态的动物模型,并随机分为两组.术后14 d及28 d,经腹腔注入HBsAg-DCs疫苗者为HBsAg-DCs组(15只),连续观察12周,注入HBsAg疫苗200 μl者为HBsAg组(15只);未予免疫抑制的LT术后Lewis大鼠为对照组(5只).切取肝脏组织行光、电镜检查;RT-PCR检测脾脏白细胞介素(IL)-2、干扰素(IFN)γ mRNA表达水平;酶联免疫吸附法检测血清IL-2、IFN γ及抗-HBs水平.两组间比较采用t检验,多组间比较采用单因素方差分析.结果 大剂量FK506使HBsAg-DCs组及HBsAg组动物处于高度免疫抑制状态,肝脏无排斥反应、IL-2及IFN γ表达水平明显低于对照组,t值为21.35～48.74,P值均<0.05; HBsAg-DCs组在疫苗注射后1、2、3个月均能检测到高滴度的抗-HBs,分别为(255.24±34.16)IU/L、(145.11±12.37)IU/L、(185.43±17.18)IU/L,明显高于HBsAg组(抗-HBs几乎为0),t值分别为45.24、47.69、58.38,P值均<0.05.结论 在LT术后处于免疫抑制状态的大鼠体内,HBsAg-DCs疫苗仍能诱导出高血清滴度的抗-HBs.     

肾移植术后抗排斥药FK506的临床应用

目的研究FK506预防肾移植术后排斥反应的效果和安全性。方法肾移植患者22例,其中18例为始用组,4例为切换组。FK506起始用0.2me／(kg·d),以后逐步减量,3个月后维持血浓度于3～12μg/L水平。切换组于停用CsA24h后应用FK506,剂量和血浓度与始用组相同。同时合并应用MMF0.5g,每日3次口服,以及术后前10天大剂量甲基强的松龙静滴,第11天改强的松口服并减量,6个月后维持强的松15mg／d。所有病例均严密观察并行血尿等生化分析。结果始用组移植肾功能好,平均血肌酐水平l02μmol／L,无一例出现排斥反应。切换组中2例异常的肝功能好转;肾功能进行性减退的2例切换后,血肌酐相对稳定。有血糖升高4例和高血压5例,用药后能控制,其他副反应有上呼吸道和下尿路感染、胸痛、恶心、呕吐、腹泻、腹部不适等。结论FK506是肾移植术后有确切疗效的基础抗排斥药,与MMF、皮质醇合用能有效地预防急性排斥的发生,并可控制慢性排斥的进展。应用剂量适当,无明显的肝、肾毒副作用,但有血糖升高及高血压副作用,药物可以控制。其它呼吸道、尿路、消化道和神经系统副反应轻,不妨碍临床用药。     

Pretreatment with FK506 improves survival rate and gas exchange in canine model of acute lung injury

The novel effects of FK506 on shock induced by lipopolysaccharide and phorbol myristate acetate (LPS/PMA) were studied using beagles. Five groups were studied: endotoxin shock control group (both 0.5 mg/kg of LPS and 30 microg/kg of PMA, n = 6); methylprednisolone-treated endotoxin shock group (n = 5); FK506-treated endotoxin shock groups in which intravenous infusions of FK506 at 2.5 microg/kg/h (low dose, n = 5), 8 microg/kg/h (medium dose, n = 5), and 25 microg/kg/h (high dose, n = 5) were administered. In the control group, the survival rate was 33%. Also, arterial hypoxemia, systemic hypotension, and marked increases in pulmonary vascular resistance (PVR) and wet-to-dry weight ratio (W/D) were observed. FK506 treatment at both medium and high doses significantly attenuated these LPS/PMA-induced physiological changes, and the survival rates were 80 and 100%, respectively. On the other hand, in the methylprednisolone group, no obvious effects were observed. The present study suggests that FK506 could have prophylactic potential against acute lung injury in endotoxin shock.     

In vivo31P nuclear magnetic resonance findings on heterotopically allografted hearts in rats treated with a novel immunosuppressant,FK 506

Administration of FK506 for 15 days at daily doses of 3.2 mg/kg p.o., 10 mg/kg p.o., 0.32 mg/kg i.m., or 1 mg/kg i.m. to heart-allografted rats resulted in a significant prolongation of graft survival time. The best graft acceptance was obtained in the 1 mg/kg i.m. group: all six grafts survived longer than 50 days, and two of them, indefinitely. The 31P nuclear magnetic resonance (NMR) technique was utilized to investigate in vivo the energy metabolism of grafts. The ratios of inorganic phosphate (Pi)/phosphocreatine (PCr) and PCr/ATP were useful parameters for monitoring cardiac insufficiency after transplantation. The mean ratios of Pi/PCr and PCr/ATP in syngeneic grafts were 0.38 +/- 0.11 and 1.88 +/- 0.42, respectively. In the control allografts, a rapid increase in the Pi/PCr ratio and a decrease in the PCr/ATP ratio were found from day 5. During the period of FK506 administration, increased Pi/PCr and decreased PCr/ATP ratios were also observed in all groups. The changes in these ratios were related with FK506 dosage. The results suggest that FK506 has a side-effect on graft metabolism. The metabolism tended to improve upon cessation of the drug in all grafts, but it worsened again in 3-3 1/2 weeks in the rats treated with 3.2 mg/kg p.o., 10 mg/kg p.o., or 0.32 mg/kg i.m. This seemed to be due to graft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunosuppressive effect of FK506 on experimental allergic neuritis in Lewis rats: change of T cell subsets.

The effect of a new immunosuppressant, FK506, on experimental allergic neuritis (EAN) was examined in Lewis rats. EAN was induced by inoculation with bovine peripheral myelin. The EAN rats were divided into two groups. FK506-treated EAN rats were prophylactically administered FK506 by injection into the peritoneal cavity at a dosage of 5.0 mg/kg/day for 13 days beginning the day after inoculation. The control EAN rats were injected with only saline solution. FK506 prevented the development of EAN, histologically and clinically. In FK506-treated EAN rats, flow cytometric analysis of T cell subsets of the lymph nodes showed a significant decrease in W3/13 positive T cells on the 14th and 21st day and a decrease in W3/25 positive T cells on the 21st day after inoculation when compared with the control EAN rats. The percentage of OX-8 positive T cells were not significantly different between the two groups. Our results suggest that FK506 prevented the development of EAN by decreasing W3/13 and W3/25 positive T cells.     

Preventive Effect of FK 506 (Tacrolimus Hydrate) on Experimentally Induced Acute Liver Injury in Rats

The aim of the study was to investigate the effect of the immunosuppressant FK 506 (tacrolimus hydrate) on acute liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS). Acute liver injury was induced in male Wistar rats by injecting the animals with P. acnes (10 mg/rat), and administering LPS (10 g/rat) seven days later. One group was given FK 506 (1 mg/kg) 24 and 2 hr before administration of LPS, and the other group was given the same dose of saline. The 24-hr survival rate, serum alanine aminotransferase (ALT) concentration, and tumor necrosis factor (TNF) - mRNA and protein concentrations in the liver and spleen were then compared. Hepatic macrophages were also isolated from rats seven days after P. acnes injection, LPS, and FK 506 or saline were added to the culture supernatant, and TNF- production was studied. The 24-hr survival rate was 100% in the FK 506-treated group, in contrast with 16.6% in the saline group. Four hours after LPS injection, the serum ALT concentration was 755 ± 401 in the saline group versus 119 ± 42 units/ml (P < 0.01) in the FK 506-treated group. The serum TNF- concentration was lower in the FK 506-treated group (1419 ± 957 pg/ml) than in the saline group (9205 ± 2215) (P < 0.01). The mRNA and protein concentrations in the liver and spleen in the two groups did not differ significantly 1 hr after LPS injection but were significantly lower in the FK 506-treated group after 4 hr. FK 506 did not directly inhibit TNF- production by isolated cultured hepatic macrophages. FK 506 is unable to inhibit initial TNF- production by hepatic macrophages (or probably that by splenic macrophages either) stimulated by injection of LPS in P. acnes + LPS-induced acute liver injury. However, the immunosuppressant does limit hepatic damage by inhibiting subsequent aggravation of inflammation by the cytokine network.     

Mycophenolate mofetil and FK506 have different effects on kidney allograft fibrosis in rats that underwent chronic allograft nephropathy

ABSTRACT: BACKGROUND: Tacrolimus (FK506) is associated with renal fibrosis in long-term use. Mycophenolatemofetil (MMF) can also inhibit or attenuate the progression of renal fibrosis. This study aimed to determine the different effects of FK506 and MMF on fibrosis-associated genes in the kidney in rats that underwent chronic allograft nephropathy (CAN). METHODS: Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. All recipients were given Cyclosporin A (CsA) 10 mg/kg-1.d-1 x 10 day and were then randomly divided into three oral treatment groups (n = 9 in each group): (1) the vehicle group was given vehicle orally; (2) the FK506 group was given 0.15 mg/kg-1.d-1 FK506; and (3) the MMF group was given 20 mg/kg-1.d-1 MMF. At 4, 8, and 12 weeks post-transplantation, serum creatinine (SCr), collagen deposition, Connective tissue growth factor (CTGF), alpha smooth muscle actin (alpha-SMA) and E-cadherin expressions were determined and hematoxylin-eosin (HE) and Periodic acid-Schiff (PAS) stains were performed. RESULTS: Renal function progressively deteriorated and showed typical CAN morphology in the vehicle and FK506 groups, while SCr and inflammatory infiltration (Banff score) showed a significant decrease in the MMF group after 8 weeks post-transplantation compared with those in the other groups (p < 0.05). Furthermore, expression levels of CTGF and alpha-SMA in the MMF group were significantly reduced, and the down-regulated expression of E-cadherin was abated (p < 0.05). CONCLUSIONS: MMF showed favorable effects on renal interstitial fibrosis, thus efficiently retarding the progression of CAN.     

FK506 inhibits human lymphocyte migration and the production of lymphocyte chemotactic factors in liver allograft recipients

The macroglide immunosuppressant FK506 is effective at preventing and reversing hepatic allograft rejection. The establishment of graft rejection is dependent upon an influx of lymphocytes from the circulation into the graft in response to locally secreted chemotactic factors. Thus, inhibition of lymphocyte migration might be an additional mode of action of FK506 that could block lymphocyte recruitment to rejecting liver allografts. In the present study, we provide evidence to support this hypothesis because we have demonstrated, using in vitro migration assays, that FK506 can inhibit the migration of lymphocytes, including CD4+ and CD8+ T-cells, to structurally diverse chemotactic factors that are present during human liver allograft rejection. In addition, FK506 acts on lymphocytes in patients with graft rejection to inhibit migration and to block the secretion of chemotactic factors in vitro. Thus, FK506 might reverse established graft rejection by inhibiting lymphocyte recruitment to the graft in vivo. (Hepatology 1996 Jun;23(6):1476-83)     

FK506和环孢素A对肾移植患者血脂的影响

目的研讨FK506和环孢素A(CsA)对肾移植术后患者脂质代谢的影响。方法对我们近三年以FK506或CsA为主要免疫抑制剂的肾移植患者术后1年血脂变化进行统计及初步分析,明确两组患者脂质代谢的不同之处。结果CsA组(198例)术后患者血脂增高的比例明显高于FK506(36例,17.17％ vs 2.78％,P＜0.05)且CsA组血脂增高患者的手术前、后血脂水平亦有明显差异(4.3±1.2mmol／L vs 4.9±1.6mmol／L,P＜0.01)。结论肾移植患者术后应用FK506比CsA可以有效降低高脂血症的发病率。     

Protective Effect of FK506 on Myocardial Ischemia/Reperfusion Injury by Suppression of CaN and ASK1 Signaling Circuitry

We investigated protective effect of FK506 on rat hearts subjected to ischemia/reperfusion (I/R) injury by regulating CaN and ASK1. Wistar rats were divided into four groups: Ischemia/reperfusion group (I/R), FK506 + Ischemia/reperfusion group (FK506-I/R), sham group, and FK506 + sham group (FK506-sham). Ischemia/reperfusion was achieved by occluding left coronary artery for 30 min and subsequently reperfusing for 120 min. FK506 was administered 15 min before ischemia. Rats in sham group and FK506-sham group were operated only by placing a ligature around the coronary artery, and the blood supply was not blocked. I/R group showed a rapid increase in TUNEL-positive cells and high risks of histopathological changes in damaged cardiac tissues. FK506 reduced the infarct size and inhibited the activation of CaN enzyme in FK506-I/R group. Increase in Bcl-2/Bax ratio in FK506-IR group indicated that FK506 protected myocardium from apoptosis induced by IR. The activity of CaN and ASK1 protein level decreased significantly after I/R injury in FK506-treated I/R heart. FK506 suppresses the activation of CaN and ASK1 through CaN-mediated apoptosis pathway, and ASK1 negatively regulates CaN activity. Suppression of CaN and ASK1 signaling circuitry are involved in protective effect of FK506 on rat myocardium I/R injury.     

肾移植受者FK506治疗窗浓度的临床观察

目的：寻求适合国人肾移植受者ＦＫ５０６理想治疗窗浓度范围。方法：应用ＥＬＩＡ法测定口服ＦＫ５０６ １２ｈ后全血谷浓度。结果：统计资料显示，术后第１个月应为１２～１８μｇ／Ｌ，第２～３个月为８～１３μｇ／Ｌ；第４个月后为５～８μｇ／Ｌ。结论：此浓度范围既能达到满意的免疫抑制效果，又有减少排斥反应和ＦＫ５０６肾毒性。     

Response of refractory colitis to intravenous or oral tacrolimus (FK506)

Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative (n = 33) or indeterminate (n = 5) colitis. FK506 was started intravenously in the first group (n = 18) at a dose of 0.01 to 0.02 mg/kg up to 14 days, followed by 0.1 to 0.2 mg/kg orally, or was started orally at this dose in a second group (n = 20). Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients, followed by a dose reduction of FK506. Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety. Primary objectives were the induction of remission (Truelove index of mild) and colectomy-free survival. Treatment lasted for a mean of 7.6 months, and the mean observation period was 16.2 months. Eighteen of 38 patients improved within 14 days, and a complete remission was achieved in 13 patients after 1 month. A colectomy within 1 month was performed in 3 of 38 patients. The overall colectomy rate was 34%. One-half of the patients with a minimum follow-up of 2 years required a colectomy. Intravenous and per oral administration were equally safe and effective. The most frequent adverse events included tremor, hyperglycemia, hypertension, and infection, but none were severe. Renal impairment was rare and subsided upon drug withdrawal. In conclusion. FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration.     

Effect of FK506 nanospheres on regeneration of allogeneic nerve after transplant

Objective:To discuss effect of FK506 nanospheres used at different time on the regcneration of allogeneic nerve after transplant.Methods:Single emulsion-solvent evaporation method(0/W) was adopted to prepare the FK506 nanospheres and the tibial nerve of rats after allogeneic transplantation.FK506 nanospheres were used in group A after operation immediately,in group B in 24 h after operation,and in group C in 3 d after operation while FK506 nanospheres were not used in group D:in the 4th,8th and 12th week after operation respectively,general observation of transplanted nerves,histological examination,image analysis of myelinated fibers,wetweight determination of musculi triceps surae,retrogradely labeling of neurons by the fluorescein and electrophysiological comparison of bilateral tibial nerve were carried out.Results:FK506nanospheres can be degraded and absorbed quickly.The neural regenerations in group A and B were similar,which were both much belter than those in group C and D.The difference was statistically significant and so was the difference between group C and D.Conclusions:Drug release rate of FK506 nanospheres is accordant with the regeneration law of damaged nerves and the local application can promote the regenerations of nerves.The effect would be better if the drug is used in earlier period(within 24 h).     

Evidence for impaired glucose effectiveness in cirrhotic patients after liver transplantation

To evaluate the impact of acute and chronic liver disease and single immunosuppression (cyclosporine A [CSA] or FK506) on insulin sensitivity and glucose effectiveness in liver-grafted patients, we performed a frequently sampled intravenous glucose tolerance test (FSIGTT) in nondiabetic patients after orthotopic liver transplantation (OLT) with acute liver failure ([ALF] group, n = 9, with CSA therapy), in patients after OLT with chronic liver disease (CSA group, n = 8; FK506 group, n = 8), and in 9 healthy control subjects. Insulin sensitivity and glucose effectiveness were determined by analyzing glucose and insulin data from the FSIGTT with Bergman's minimal model technique for glucose. The intravenous glucose tolerance index ([KG] ie, the slope of the regression of the logarithm of blood glucose concentration) was not different between the ALF group (2.17 +/- 0.16 min(-1)) and controls (2.29 +/- 0.13 min(-1)), but was lower (P < .05) in both groups with chronic liver disease (CSA group, 1.46 +/- 0.1; FK506 group, 1.61 +/- 0.11 min(-1)) compared with the ALF group (P < .05). A positive relation for the KG and glucose effectiveness was found in all liver-grafted patients and controls. Insulin sensitivity was not different between all liver-grafted patients and controls. The body mass index (BMI) was the overall determinant of insulin sensitivity in all groups. Single immunosuppressive therapy does not impair insulin sensitivity in liver-grafted patients. The lower glucose effectiveness in liver-grafted patients with chronic liver disease but not in patients after ALF points to a defect in the regulation of glucose-mediated glucose uptake in peripheral tissue.     

Predominant inhibition of Th1 cytokines in New Zealand black/white F1 mice treated with FK506

The T-helper 1/T-helper 2 (Th1/Th2) cell balance was examined in 6-month-old New Zealand black/white F1 (B/WF1) mice treated with an immunosuppressive agent, FK506. The survival rate of mice treated with 10 mg/kg/day of FK506 was 7/8, while that of those treated with 2.5 mg/kg/day was 5/8, and 4/8 after treatment for 8 weeks with placebo. Proteinuria, which was already positive in all mice before the treatment, in the seven of eight mice treated with 10 mg/kg/day remained mildly positive (< or = 1+), while seven of eight mice treated with 2.5 mg/kg/day and six of eight mice treated with the placebo showed severe proteinuria (> or = 2+). Pathological changes in the kidneys of mice treated with 10 mg/kg/day of FK506 were less severe than in mice treated with the placebo or 2.5 mg/kg/day of FK506. Expression of mRNA was unchanged for all cytokines determined in the groups treated with 2.5 mg/kg/day of FK506 or placebo. In contrast, expression of mRNA for interleukin (IL)-2, and interferon (IFN)-gamma was suppressed, while that for IL-4 and IL-10 was not suppressed in the group treated with 10 mg/kg of FK506. The serum levels of IgG-class anti-DNA antibodies, which had been elevated before the treatment, were suppressed--especially in the IgG2a subclass--and the deposition of IgG2a and IgG2b in the glomeruli was reduced in the group treated with 10 mg/kg/day of FK506 compared with the other groups. These findings suggest that an improvement in the lupus nephritis of 6-month-old B/WF1 mice induced by FK506 might be associated with a predominant inhibition of Th1 cytokine.     

Dynamic alterations in the gut microbiota and metabolomeduring the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis

AIM To investigate changes in gut microbiota and metabolism during nonalcoholic steatohepatitis(NASH) development in mice fed a methionine-choline-deficient(MCD) diet. METHODS Twenty-four male C57 BL/6 J mice were equally divided into four groups and fed a methionine-choline-sufficient diet for 2 wk(Control 2 w group,n = 6) or 4 wk(Control 4 w group,n = 6) or the MCD diet for 2 wk(MCD 2 w group,n = 6) or 4 wk(MCD 4 w group,n = 6). Liver injury,fibrosis,and intestinal barrier function were evaluated after 2 and 4 wk of feeding. The fecal microbiome and metabolome were studied using 16 s r RNA deep sequencing and gas chromatography-mass spectrometry. RESULTS The mice fed the MCD diet presented with simple hepatic steatosis and slight intestinal barrier deterioration after 2 wk. After 4 wk of feeding with the MCD diet,however,the mice developed prominent NASH with liver fibrosis,and the intestinal barrier was more impaired. Compared with the control diet,the MCD diet induced gradual gut microbiota dysbiosis,as evidenced by a marked decrease in the abundance of Alistipes and the(Eubacterium) coprostanoligenes group(P 0.001 and P 0.05,respectively) and a significant increase in Ruminococcaceae UCG 014 abundance(P 0.05) after 2 wk. At 4 wk,the MCD diet significantly reduced the promising probiotic Bifidobacterium levels and markedly promoted Bacteroides abundance(P 0.05,and P 0.01,respectively). The fecal metabolomic profile was also substantially altered by the MCD diet: At 2 wk,arachidic acid,hexadecane,palmitic acid,and tetracosane were selected as potential biomarkers that were significantly different in the corresponding control group,and at 4 wk,cholic acid,cholesterol,arachidic acid,tetracosane,and stearic acid were selected. CONCLUSION The MCD diet induced persistent alterations in the gut microbiota and metabolome.     

他克莫司治疗移植肾慢性排斥的初步临床观察

目的：探讨他克莫司（FK506）、环孢素A（CsA)治疗移植肾慢性排斥（CR)的可行性及安全性。方法：40例同种异体肾移植患者肾功能减退经病理证实为CR，随机分为CsA切我为FK506组20例、继续使用CsA组20例。观察各组移植肾功能、肾小球滤过率、蛋白尿、血压、血脂变化及急性排斥（AR）发生率，治疗后随访12个月。结果：追踪12个月，FK506组16例移植肾功能稳定（80％）；3例行血液透析治疗，1例死亡，人存活率95％。CsA组15例移植肾功能稳定，3例行血液透析治疗，逆转成功率75％；2例死亡，人存活率90％。结论：FK506可以延缓慢性移植物失功。FK506的使用是安全和有效的。     

Studies on mechanisms of augmentation of liver regeneration by cyclosporine and FK 506.

Evidence could not be found of immune modulation of liver regeneration. The powerful immunosuppressive drug FK 506, which augments the response after partial hepatectomy in normal rats, had the same effect in T cell-deficient nude rats. The cytotoxicity of natural killer cells in treated nude rats was not significantly changed by FK 506 therapy. However, the serum of FK 506-treated nude rats increased hepatocyte proliferation when added to third-party hepatocyte cultures, suggesting that FK 506 had induced a serum growth factor in the nude rats or had suppressed an inhibitory factor. A hypothesis was advanced that FK 506 (and cyclosporine) affects hepatic growth by nonimmunological pathways.     

FK 506 ameliorates the hepatic injury associated with ischemia and reperfusion in rats.

The effect of FK 506 on regeneration of the liver was studied in rats after a two-thirds partial hepatectomy after 60 min of ischemia of the unresected liver. The animals were divided into three distinct groups of 10 rats each. Group 1 (controls) received 0.5 ml saline solution intravenously 30 min after the induction of ischemia. Groups 2 and 3 were injected with FK 506 (0.3 mg/kg) intravenously 30 min after and 24 min before the induction of hepatic ischemia, respectively. The hepatic content of ATP and serum levels of ALT and lactate dehydrogenase were determined on each animal. In addition, the histological appearance and mitotic activity of the remnant liver was determined at regular 24-hr intervals after hepatic ischemia. All 10 control animals died within 72 hr. Treatment with FK 506 resulted in improved survival in groups 2 and 3 (30% and 80%, respectively). The improved survival seen in the FK 506-treated animals was reflected by a restoration of hepatic ATP content, a reduction in the serum levels of ALT and lactate dehydrogenase, an amelioration of hepatic necrosis and neutrophilic infiltration and an increase in the mitotic activity of the liver. These results suggest that FK 506 ameliorates the hepatic injury associated with ischemia/reperfusion and has a potent stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective agent when administered to organ donors before graft harvesting.     

Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation

Ischemia/reperfusion (I/R) injury remains a key risk factor significantly affecting morbidity and mortality after liver transplantation (LT). B7 homolog 1 (B7-H1), a recently identified member of the B7 family, is known to play important roles in regulating local immune responses. We hypothesized that B7-H1 plays crucial roles during innate immune responses induced by hepatic I/R injury, and using B7-H1 knockout (KO) liver grafts, we tested this hypothesis in the mouse LT model with 24 hours of cold storage. Cold I/R injury in wild type (WT)-to-WT LT enhanced constitutive B7-H1 expression on dendritic cells and sinusoidal endothelial cells and promptly induced B7-H1 on hepatocytes. When B7-H1 KO liver grafts were transplanted into WT recipients, serum alanine aminotransferase (ALT) and graft necrosis levels were significantly higher than those after WT-to-WT LT. Augmented tissue injury in B7-H1 KO grafts was associated with increased frequencies and absolute numbers of graft CD3(+) T cells (particularly CD8(+) T cells). B7-H1 KO grafts had significantly fewer annexin V(+) CD8(+) T cells, and this indicated a failure to delete infiltrating CD8(+) T cells. To evaluate the relative contributions of parenchymal cell and bone marrow-derived cell (BMDC) B7-H1 expression, we generated and transplanted into WT recipients chimeric liver grafts lacking B7-H1 on parenchymal cells or BMDCs. A selective B7-H1 deficiency on parenchymal cells or BMDCs resulted in similar levels of ALT and liver injury, and this suggested that parenchymal cell and BMDC B7-H1 expression was involved in liver damage control. Human livers up-regulated B7-H1 expression after LT. CONCLUSION: The study demonstrates that graft tissue expression of B7-H1 plays a critical role in regulating inflammatory responses during LT-induced hepatic I/R injury, and negative coregulatory signals may have an important function in hepatic innate immune responses.