OKT3 prophylaxis in liver transplantation

In a randomized prospective study of liver transplant recipients, we compared prophylaxis with OKT3, steroids, and azathioprine to cyclosporine, steroids, and azathioprine. Seventy-two percent of patients receiving OKT3 prophylaxis were rejection free in the first 14 days compared to 41% in the cyclosporine group (P=0.02). However, after 14 days through a mean of 6.3 months, the overall incidence of rejection did not differ between the two groups (74% for the cyclosporine group and 48% for the OKT3 group). There was no increase in the rate of infectious complications noted in the OKT3-treated group. Thirty-nine percent of the OKT3-treated patients developed anti-OKT3 antibodies. Eight patients in the OKT3 group required reuse of OKT3 for rejection. Six of these continued to have greater than 10% CD3-positive cells with retreatment. Five were rescued successfully. With a mean survival of greater than 674±209 days in the OKT3-treated group and 626±242 days in the cyclosporine-treated group, no overall differences in graft and patient survival, liver function, renal function, late rejection incidence, or infectious complications were evident between the two groups. We conclude that OKT3 offers no long-term benefit compared to cyclosporine prophylaxis and should be reserved for treatment of rejection in patients in whom cyclosporine may be contraindicated.     

Prophylactic use of OKT3 in liver transplantation

Liver rejection in the era of cyclosporine-based immunosuppression is approximately 60–70%. Approximately 15–25% of liver transplant patients will require hemodialysis following transplantation. These facts argue for a potent, less nephrotoxic immunosuppressive regimen, especially during the period of vulnerability to these events. Prophylactic use of OKT3 has been suggested as a means to decrease the need for hemodialysis while maintaining potent immunosuppression. The goal of this review is to examine potential benefits and pitfalls of this regimen. A lack of documentation of long-term patient and graft survival, the potential susceptibility to infectious complications, development of sensitization, and the cost must be weighed against the decreased need for hemodialysis and the control of early rejection episodes.     

Muromonab-CD3 therapy for refractory rejections after liver transplantation: a single-center experience during two decades in Japan

Background/purpose

Refractory rejections still occur in the liver transplantation (LT) field. The aim of this study was to investigate significant factors for the introduction of therapy with muromonab-CD3 (MCD3) after LT.

Methods

A total of 1415 LT patients were retrospectively evaluated, and 11 of the recipients received MCD3 therapy because of steroid-resistant rejections. The clinical factors before LT and before MCD3 therapy were investigated.

Results

The recipients were retrospectively divided into two groups based on responses to MCD3 therapy, including their clinical courses after MCD3 therapy and their outcomes. The MCD3 therapy had positive effects in LT recipients with the following four factors: low score of model for end-stage liver disease or pediatric end-stage liver disease; earlier time point of the first incidence of rejection; more frequent steroid pulse therapy (SPT) within 2 weeks after LT; and the expression of CD3 in the peripheral blood before MCD3 introduction.

Conclusion

Optimal induction of MCD3 triggered recovery from refractory rejections, especially in LT recipients in a stable condition, but not in those in a critical or compromised condition.     

OKT3治疗肝移植术后激素冲击无效的急性排斥反应

我中心自2004年1月至2006年12月有3例肝移植患者，出现急性排斥反应后经激素冲击治疗无效，使用OKT3后逆转，现总结如下。[第一段]     

Late-onset acute rejection after living donor liver transplantation

INTRODUCTION Standard regimens for immunosuppressive therapy after liver transplantation include calcineurin inhibitors and steroids, which result in a reduced incidence of acute rejection and improved recipient survival[1]. The long- term complications o…     

Vitamin D and the risk of acute allograft rejection following human liver transplantation

Background: Vitamin D may act as an immune modulator in experimental and human organ transplantation, but these data are yet to be confirmed in human liver transplantation (LT). Aim: This study aimed to assess the relationship between acute liver allograft cellular rejection (ACR) and pretransplant serum vitamin D concentration or post‐transplant vitamin D supplementation. Method: We studied 133 LT recipients who underwent two per protocol allograft biopsies in the early post‐operative period, plus on‐demand biopsies as clinically indicated. ACR estimate was given according to the Banff scheme in biopsies obtained along two follow‐up periods: (a) from the transplant operation to the end of the second month (0–2 months); (b) and from the third month to the end of the eighth month (3–8 months) post‐LT. Results: The median pretransplant serum 25‐hydroxyvitamin D concentration was 12.5 ng/ml; 40 patients had concentrations ≤12.5 ng/ml, of whom six had ≤5.0 ng/ml. Seventy‐nine recipients received oral vitamin D₃ supplementation to treat post‐transplant osteoporosis. In the 0–2 months period, moderate‐to‐severe rejection episodes were independently associated with cytomegalovirus reactivation (P<0.005) and progressively lower pretransplant serum 25‐hydroxyvitamin D concentrations (P<0.02). Early vitamin D₃ supplementation was independently associated with a lack of ACR (P<0.05). Conclusions: These results suggest that vitamin D may favour immune tolerance towards the liver allograft.     

Experiences with monoclonal antibody orthoclone OKT3 following liver transplantation]

In 7 patients 10 cycles (5 to 21 days, dosage: 30 to 430 mg, median 138 mg) of OKT3 therapy were performed after liver transplantation. In all patients reactivation of an EBV-infection with hepatitis was observed. Two patients treated with high dosages (430 mg respectively 195 mg) developed lymphoproliferative lesions. In one patient with persistent EBV-infection (dosage: 360 mg) a B-cell-lymphoma was diagnosed. This patient died 26 months after transplantation.     

Immunohistochemical staining of liver grafts with a monoclonal antibody against HCV-Envelope 2 for recurrent hepatitis C after living donor liver transplantation

Aim:  We evaluated the expression of hepatitis C virus (HCV) antigen on liver grafts by immunohistochemical staining (IHS) using IG222 monoclonal antibody (mAb) against HCV-envelope 2 (E2).
Methods:  The study material was 84 liver biopsy specimens obtained from 28 patients who underwent living donor liver transplantation (LDLT) for HCV infection. The biopsy samples were examined histopathologically, and by IHS using IG222 mAb against HCV-E2. Serum HCV-RNA level was measured in all patients. The IHS grades were compared among the three groups classified according to the time elapsed from LDLT (at 1–30, 31–179 and ≥180 days post-LDLT) and among four post-transplant conditions, including acute cellular rejection (ACR).
Results:  Immunoreactivity to IG222 was detected in 78.6% of the specimens obtained during the first month after LDLT, and there were no significant differences on the IHS grades between the three groups classified according to the time elapsed from LDLT. The IHS grades were significantly stronger in definite recurrent HCV ( n  = 12) and probable recurrent HCV ( n  = 7) than in definite ACR ( n  = 7) and other complications ( n  = 8). There were no significant differences in serum HCV-RNA levels among the four post-transplant conditions. There was no significant correlation between the IHS grades using IG222 mAb and serum HCV-RNA levels when data of 84 liver biopsy specimens were analyzed.
Conclusions:  Constant HCV-E2 expression was observed in liver biopsy specimens obtained 1 month or longer. The strong HCV-E2 expression on liver grafts were associated with recurrent hepatitis C after LDLT, but the serum HCV-RNA levels were not.     

PNPLA3 as a liver steatosis risk factor following living‐donor liver transplantation for hepatitis C

Aim

Liver steatosis frequently occurs following liver transplantation (LT) and can affect patient outcome. Here, we aimed to clarify the steatosis and steatohepatitis risk factors that apply after living‐donor LT for chronic hepatitis C.

Methods

We retrospectively examined 43 transplant recipients and donors, and tested for single nucleotide polymorphisms in the PNPLA3 gene. Liver biopsies taken 1 year after transplantation and yearly thereafter, or when abnormal liver enzyme levels were detected, were examined by histopathology.

Results

Liver steatosis (>5% steatotic hepatocytes) was evident in 13 of 43 cases (30%), and steatohepatitis in 3 (7.0%). The average time to steatosis after LT was 2.74 ± 1.55 years. The PNPLA3 rs738409 GG genotype, a steatosis risk factor, was identified in 13 recipients and 10 donors. Steatosis prevalence did not differ according to recipient genotype. However, this condition was significantly more common among patients who received tissue from donors carrying the rs738409 GG genotype compared to those with grafts from donors of the CC or CG genotype (60, 7, and 26%, respectively; P < 0.05). All 3 steatohepatitis cases were associated with the GG donor genotype.

Conclusion

The PNPLA3 rs738409 GG donor genotype affects liver steatosis and steatohepatitis risk following living‐donor LT.     

Cytomegalovirus infection and disease after liver transplantation

Cytomegalovirus is the single most important pathogen in clinical transplantation. Although much progress has been made in our understanding of the molecular biology and epidemiology of CMV infection and in our ability to diagnosis and treat CMV disease, it remains a major cause of morbidity but is no longer a major cause of mortality after liver transplantation. Risk factors for CMV disease after liver transplantation include donor and recipient serologic status, the use of antilymphocyte therapy, and retransplantation. CMV disease occurs early after transplantation, and the most frequent site of disease is the hepatic allograft. We have treated 79 patients with intravenous ganciclovir, with ultimate control of disease achieved in 69 patients (87.3%). Preliminary results using intravenous immunoglobulin and oral acyclovir for CMV prophylaxis in high-risk patients have been encouraging. In addition to producing clinical syndromes, CMV may have direct immunologic effects and is a marker of the net state of immunosuppression.     

肝移植急性排斥反应的生化诊断

目的　总结肝移植术后急性排斥反应 (AR)的诊断经验。方法　回顾性分析 70例肝移植患者术后AR的发生率 ;分析AR组、保存 再灌注损伤 (PRI)组移植肝活检前患者生化检测值。结果　 42例次移植肝活检 ,17次发生AR ,2 2次为PRI ;3次为药物中毒。生化检测AR组 ,随发病进展 ,ALT、AST逐渐增高 ,成正相关 (P <0 .0 5 ) ;PRI组随发病进展 ,ALT、AST逐渐降低 ,成负相关 (P <0 .0 5 )。结论　移植肝活检及活检前生化检测对于AR的诊断与鉴别诊断有重要意义。     

Expression of CD44 in rat liver allografts during rejection

As CD44 is believed to be a homing receptor involved in lymphoid trafficking and inflammatory responses, it is expected to be closely linked to transplant rejection. In this study, the expression of CD44 during liver transplant rejection was compared with the expression of lymphocyte-function associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), which play an essential role in cell interactions and the initiation of immune responses. Male Brown Norway (BN) and Lewis (LEW) rats were used as donors and recipients, respectively. Orthotopic liver transplantation (OLTX) was done using the cuff technique of Kamada and Calne. Animals were killed on days 3, 5, and 7 after OLTX, and a piece of tissue from each of the liver grafts was obtained. Immunohistochemical staining was used to investigate the expression of CD44, ICAM-1, and LFA-1. CD44 was strongly expressed in portal areas of the rejected liver, and LFA-1 and ICAM-1 were expressed mainly on sinusoids and hepatocytes. These findings indicate that CD44 is closely involved in lymphocyte infiltration, which is dominant in portal areas, and that lymphocyte infiltration during the rejection process may involve a homing mechanism.     

Liver allograft radiotherapy to treat rejection in children: efficacy in orthotopic liver transplantation and long-term safety.

BACKGROUND: We studied, retrospectively, the efficacy to control rejection and long-term safety of liver allograft radiotherapy (RT) performed in 14 children. Long-term safety data were collected with the prospect of possible use of RT in liver cell transplantation (LCT). METHODS: Immune suppression included cyclosporine, azathioprine and prednisone. In case of intractable rejection, low-dose allograft RT was administered daily for 3 days, and short-term efficacy was evaluated by liver enzyme assays and histology. The long-term outcome was compared with that of 122 patients undergone transplantation and who had similar treatment, but no RT. RESULTS: Survival at 15 years was 71.4% vs 69.7% in the comparison group. In the RT group, rejection control was complete in six of 14 children and partial in two, all being alive and well 14-18 years later. Ten of 14 children had follow-up biopsy. Six children had normal histology and four had mild unspecific fibrosis. The long-term follow-up biopsy in the comparison group showed fibrosis in 42 of 85 children. The incidence of complications was similar in both groups. CONCLUSIONS: This series shows that, such a RT regimen appeared to be efficient and safe as a rescue treatment for acute rejection. Provided that further investigations in animal models show a certain benefit of low-dose irradiation around LCT, such a regimen could be proposed in human liver cell transplant programmes.     

熊去氧胆酸辅助预防肝移植排斥的临床研究

目的研究熊去氧胆酸(优思弗)对原位肝移植的急性排斥反应、感染率、住院治疗时间及90d存活率的影响。方法总结105例肝移植患者的临床资料,优思弗治疗组78例,未使用优思弗27例为对照组;所有患者均使用他克莫司(FK506)或皮质类固醇作为免疫抑制剂。结果治疗组急性排斥反应多次发作的病例数显著小于对照组(2:7,P=0.01),严重的细菌感染率明显降低(3%:33%,P=0.01),住院时间明显缩短(34d:47d,P=0.03)和更高的90d存活率(97%:85%,P=0.04)。结论基于FK506的免疫抑制疗法中加入优思弗,可减少肝移植急性排斥反应的发作次数,值得推荐。     

受体骨髓间质干细胞在大鼠原位肝移植中对免疫排斥的影响

目的:观察受体骨髓间质干细胞(BM-MSCs)在大鼠原位肝移植后体内的分布与作用.方法:以Wistar大鼠为供体,SD大鼠为受体采用双袖套法制作原位肝移植模型,密度梯度离心法分离与贴壁法富集受体BM-MSCs.CFSE标记术后经门静脉注入,荧光显微镜分别观测术后1wk,2 wk,1mo肝脾肺肾组织中BM- MSCs的分布及各时间点检测肝功能及肝组织免疫排斥情况.结果:密度梯度离心所得到的BM-MSCs为比较一致的球形单个核细胞,台盼蓝染色细胞活力达98%左右,其他细胞少见.BM-MSCs体外分离培养扩增至第3代后较为纯化.应用CFSE可快速高效的标记贴壁BM-MSCs.移植的BM-MSCs主要在受体肝脏中聚集,1mo后略有减少,而脾肺肾组织内BM-MSCs在1mo后仅有极少分布.B组无BM-MSCs输入与C组有BM-MSCs输入肝功能比较,C组肝功能有明显好转,B,C组间差异有显著意义(F=63.179,P<0.01),B,C组各时段肝功能差异有显著性意义(F=221.026,P<0.01).C组肝组织免疫排斥反应明显减轻.结论:原位肝移植术后输注受体BM-MSCs可有效缓解免疫排斥反应.     

Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody

OKT3 monoclonal antibody is a murine monoclonal antibody specific for the T lymphocyte T3 cell surface receptor that mediates antigen recognition. The use of OKT3 monoclonal antibody for the treatment of cardiac allograft rejection refractory to conventional therapy with high-dose steroids and antithymocyte globulin is described. Seven patients received 5 mg of OKT3 monoclonal antibody intravenously per day for 10 to 14 days. Diagnosis of moderate or severe rejection was made in all seven from right ventricular endomyocardial biopsy. Biopsy was repeated 48 to 72 hours and seven to 10 days after OKT3 monoclonal antibody was begun. With treatment, four patients had a complete response, with improvement on both early and late biopsy. Two patients had partial responses, with improvement on early biopsy followed by worsening rejection on late biopsy. One patient died of graft failure six hours after receiving OKT3 monoclonal antibody. Adverse events were common in the first two days of therapy but were well tolerated. It is concluded that OKT3 monoclonal antibody is useful in the treatment of refractory cardiac allograft rejection.     

Using on-site liver 3-D reconstruction and volumetric calculations in split liver transplantation

BACKGROUND: Split liver transplantation increases the number of grafts available for transplantation. Pre-recovery assessment of liver graft volume is essential for selecting suit-able recipients. The purpose of this study was to determine the ability and feasibility of constructing a 3-D model to aid in surgical planning and to predict graft weight prior to anin situ division of the donor liver.
METHODS: Over 11 months, 3-D volumetric reconstruction of 4 deceased donors was performed using Pathifnder Scout? liver volumetric software. Demographic, laboratory, operative, perioperative and survival data for these patients along with donor demographic data were collected prospectively and analyzed retrospectively.
RESULTS: The average predicted weight of the grafts from the adult donors obtained from anin situ split procedure were 1130 g (930-1458 g) for the extended right lobe donors and 312 g (222-396 g) for left lateral segment grafts. Actual adult graft weight was 92% of the predicted weight for both the ex-tended right grafts and the left lateral segment grafts. The pre-dicted and actual graft weights for the pediatric donors were 176 g and 210 g for the left lateral segment grafts and 308 g and 280 g for the extended right lobe grafts, respectively. All grafts were transplanted except for the right lobe from the pediatric donors due to the small graft weight.
CONCLUSIONS: On-site volumetric assessment of donors provides useful information for the planning of anin situ split and for selection of recipients. This information may expand the donor pool to recipients previously felt to be unsuitable due to donor and/or recipient weight.     

巴利昔单抗作为免疫诱导剂预防国人心脏移植术后早期急性排斥反应的疗效和安全性的观察

目的观察国人心脏移植用巴利昔单抗作为免疫诱导剂与传统的三联免疫抑制剂合用的耐受性和预防术后早期急性排斥反应的效果。方法心脏移植患者47例,男38例,女9例,平均年龄(44.9±13.4)岁,包括扩张型心肌病20例(42.5%),缺血性心肌病12例(25.5%),致右室心律失常性心肌病8例(17.0%),肥厚型心肌病2例(4.2%),心脏肿瘤2例(4.2%),瓣膜性心肌病1例(2.1%),高血压心脏病1例(2.1%),巨细胞性心肌炎1例(2.1%)。术前淋巴细胞群体反应抗体(PRA)>10%者4例,交叉配型均<5%。用巴利昔单抗诱导治疗20mg×2次。三联免疫抑制剂用法:术中给予甲基强的松龙500mg×2次,术后125mg每8h1次;拔除气管插管后给予强的松1mg.kg-1.d-1,以后每3天减量10mg,至总量10mg/d维持。环孢素A(CsA)于术后血肌酐<150μmol/L开始服用,剂量3～6mg.kg-1.d-1,分2次服用,血药谷值浓度维持在180～300ng/ml。术后3周作1次心内膜活检。霉酚酸酯(MMF)1.0～2.0mg/d,分2次服用。急性排斥反应分级按照国际心肺移植协会(ISHLT)的标准。巨细胞病毒感染的监测用PP65抗原血症试验,EB病毒感染用ELISA方法查抗体。结果47例患者全部存活。急性排斥反应分级结果:0级30(63.8%)人,ⅠA级11(23.4%)人,ⅠB级3(6.3%)人,Ⅱ级3(6.3%)人。MMF平均剂量(1.2±0.3)g/d。CsA于术后平均(3.4±2.1)d开始服用,平均累积剂量(4.1±1.2)mg.kg-1.d-1,平均谷值浓度(237.0±76.2)ng/ml。术后1个月内感染5人,但无巨细胞病毒和EB病毒感染。结论国人心脏移植用巴利昔单抗作为免疫诱导剂与传统的三联免疫抑制剂合用的耐受性良好,预防术后早期急性排斥反应有效。