稳定的儿童肝移植患者中单次检测活化CD4^+T淋巴细胞内ATP水平的临床意义

在免疫抑制的移植患者随访过程中,通过Immuknow试验在体外检测活化的CD4+T淋巴细胞内ATP水平有助于认识免疫系统是如何发挥作用的。因此,有研究报道低ATP水平与机会性感染的发生有关。虽然数量有限,但在儿童和成人移植患者方面都已有相关的研究报道。本研究纳入40名肝移植术后1年以上的患儿进行回顾性分析,患儿均接受了Immuknow检测,其ATP平均值为317μg/L（200～400μg/L）,与以往在成人患者中测试的结果相近。接受他克莫司或环孢素单一治疗患儿的CD4+T淋巴细胞内ATP水平明显高于接受他克莫司或环孢素加吗替麦考酚酯（骁悉）联合治疗的患儿（P＝0.005）。在接受环孢素治疗的患儿中,单一治疗组与联合治疗组的ATP水平具有显著性差异（P＝0.0003）,而接受他克莫司治疗时两者间没有显著性差异（P＞0.05）。研究者认为,单一测定CD4+T淋巴细胞内ATP水平可作为一种辅助检测手段用于指导儿童肝移植患者免疫抑制剂的使用。     

肾移植术后并发巨细胞病毒肺炎患者的细胞免疫状态

目的 探讨CD4+T淋巴细胞ATP含量检测在肾移植术后并发巨细胞病毒(CMV)肺炎治疗中应用价值.方法 以187例首次肾移植受者作为研究对象,分别于术前,术后30、60、90和180d,发生CMV肺炎时,以及治疗4周后采集受者外周血,应用ImmuKnowTM免疫细胞功能测定试剂盒检测CD4+T淋巴细胞内ATP含量.采用方差分析对不同检测时间点及术后有无并发CMV肺炎者的外周血CD4+T淋巴细胞ATP含量进行比较,采用Pearson-Spearman秩和检测对ATP含量与感染的相关性进行分析.结果 187例受者中发生CMV肺炎17例,发生率为9.1 ％(17/187),发生时间为术后(2.8±1.2)个月.术后所有时间点CD4+T淋巴细胞ATP含量均明显低于术前(P＜0.01),ATP含量在术后90d时达最低点,与术后其他时间点比较,差异有统计学意义(P＜0.05).发生CMV肺炎者术前外周血CD4+T淋巴细胞ATP含量为(376±182) μmol/L,术后30和90 d分别为(283±146) μmol/L和(196±112) μmol/L,发生CMV肺炎时和治疗4周后分别为(145士102)μmol/L和(236±117) μmol/l,发生CMV肺炎时ATP含量与其他各个时间点比较,差异均有统计学意义(P＜0.05).相关分析表明,CD4+T淋巴细胞内ATP含量降低与CMV肺炎的发生具有显著相关性(相关系数=0.5106,P＜0.01).结论 肾移植后测定受者外周血CD4+T淋巴细胞ATP含量,可反映受者的细胞免疫状态及判断CMV肺炎的严重程度和临床预后,并可指导CMV肺炎的治疗.     

ImmuKnow检测免疫细胞功能在肾移植术后免疫功能监测中的应用

目的探讨Immu Know检测免疫细胞功能在监测肾移植术后患者免疫功能变化的应用价值。方法 2013年1月至2014年12月在广州医科大学附属第二医院器官移植科实施肾移植手术的106例尿毒症患者,分别于术前、术后12个月内发生感染或急性排斥反应时抽取血液标本。采用Immu Know测定CD4+T细胞内的三磷腺苷(ATP)含量。观察与比较不同临床状态肾移植患者的ATP含量,包括术前组、稳定组、急性排斥反应组和感染组(含重症肺炎)。检测外周血T细胞亚群CD4+T细胞、CD8+T细胞及自然杀伤(NK)细胞比例。采用Pearson相关分析法了解ATP值与他克莫司(FK506)和环孢素(Cs A)血药谷浓度的关系。结果感染组患者ATP含量低于术后稳定组患者(P0.001),其中发生重症肺炎患者ATP含量低于发生其他感染的患者(P0.05)。感染组患者的CD4+T细胞百分比低于稳定组患者(P0.05)。ATP含量与移植患者术后FK506和Cs A血药谷浓度无相关性。结论 Immu Know检测可用于监测肾移植患者术后免疫功能状态。CD4+T细胞内ATP含量检测对术后感染,特别是对重症肺炎有提示和预警作用。     

不同免疫抑制方案对肾移植术受者CD4~+ Foxp3~+ 调节性T细胞的影响

目的 探讨不同免疫抑制剂方案对肾移植术受者外周血CD4~+ Foxp3~+调节性T细胞(regulatory T cells,Treg)表达水平的影响.方法 定群研究了2006年1月至2008年1月在本移植中心接受初次移植50例随访满1年肾移植受者,分为钙调神经蛋白抑制组(钙调神经蛋白抑制剂+吗替麦考酚酯+强的松)19例,其中环孢素组10例,他克莫司组9例;雷帕霉素组(雷帕霉素+吗替麦考酚酯+强的松)31例.另取20例行规律血液透析终末期肾病患者为对照组.采用流式细胞仪的方法检测3组外周血CD4~+ Foxp3~+ Treg占CD4~+ T细胞的比例,比较各组间表达水平与不同免疫抑制方案的关系.结果 钙调神经蛋白抑制剂组、雷帕霉素组和终末期肾病组3组年龄、性别比无统计学差异(P>0.05).钙调神经蛋白抑制剂组、雷帕霉素组2组冷缺血时间、HLA错配率、群体反应性抗体(PRA)和急性排斥反应发生率无统计学差异(P>0.05).雷帕霉素组和终末期肾病组CD4~+ Foxp3~+ T细胞占CD4~+ T细胞的比例均明显高于钙调神经蛋白抑制组,差异有统计学意义(P<0.01).使用环孢素患者和他克莫司患者外周血中CD4~+ Foxp3~+ T细胞占CD4~+ T细胞的比例之间无显著性差异(P>0.05).结论 肾移植术后服用雷帕霉素组患者外周血CD4~+ Foxp3~+ Treg占CD4~+ T细胞的比例显著高于服用钙调神经蛋白抑制组患者,提示雷帕霉素有助于诱导宿主对移植肾免疫耐受.     

肾移植受者CD4+细胞内三磷酸腺苷的测定及意义

目的探讨CD4 细胞内ATP浓度测定在评价肾移植早期受者细胞免疫功能中的临床意义。方法采用植物血凝素刺激、单克隆抗体包被的免疫磁珠分离CD4 细胞,以Celltiter- GloTM荧光试剂标记,测定52例肾移植受者术前,术后3、7、14与30 d以及发生感染时CD4 细胞内ATP浓度,同时应用流式细胞仪检测T淋巴细胞亚群和绝对值计数(CD4 -ALC)。结果肾移植受者术前CD4 细胞内ATP浓度为(404±190)ng/ml,明显低于正常成人的(516±257)ng/ml(P< 0.05),术后1周左右降至最低,采用抗人胸腺细胞球蛋白诱导治疗者尤其明显,2周左右开始回升,4周时仍低于术前水平(P<0.01),抗体诱导者回升相对较慢。肾移植受者术前CD4 -ALC为(499±240)个/μl,明显低于正常成人的(735±370)个/μl(P<0.05);术后CD4 -ALC的变化与ATP浓度的变化趋势相仿,但二者的相关系数<0.1。术后并发肺部感染者,其CD4 细胞内ATP浓度下降,病情加重时下降更加明显,感染控制后有所回升,CD4 细胞/CD8 细胞比值有类似变化。ATP浓度与血药浓度无直接相关性(r2<0.1)。结论CD4 细胞内ATP浓度可反映机体的整体细胞免疫状态,指导临床制定治疗方案。     

阿来佐单抗行肾移植免疫诱导治疗的有效性和安全性

目的 评价阿来佐单抗行肾移植免疫诱导治疗的有效性和安全性.方法 将89例肾移植受者随机分为试验组(43例)和对照组(46例).试验组于肾移植术前和术后24 h内分别静脉滴注阿来佐单抗15 mg,对照组不接受免疫诱导治疗.受者术后常规应用环孢素A(或他克莫司)+吗替麦考酚酯+泼尼松预防排斥反应.统计两组术后12月内的移植肾功能、急性排斥反应发生率、感染发生率、移植肾功能延迟恢复发生率、移植肾存活率及淋巴细胞计数,并用ImmuKnowTM免疫细胞功能测定法检测受者CD4+T淋巴细胞的三磷酸腺苷(ATP)值.结果 术后12个月内试验组7.0%(3/43)的受者发生病理证实的急性排斥反应,明显低于对照组的23.9%(11/46,P＜0.05).试验组和对照组总体的感染发生率为别为39.5%(17/43)和30.4%(14/46,P＞0.05),两组机会性感染的发生率分另为23.2%(10/43)和17.4%(8/46,P＞0.05).术后3个月内,试验组淋巴细胞计数低于对照组;术后6个月内,试验组CD4+T淋巴细胞ATP值低于对照组.结论 阿来佐单抗行肾移植免疫诱导治疗可维持受者的免疫抑制状态,未见严重不良反应.     

肾移植后使用西罗莫司继发间质性肺炎七例

目的 分析肾移植术后使用西罗莫司(SRL)的受者继发间质性肺炎的情况,以指导临床治疗。方法 7例肾移植受者在使用SRL后发生间质性肺炎8次,其中2例初始免疫抑制治疗即采用含SRL的方案,5例的初始免疫抑制方案为他克莫司（或环孢素A）+吗替麦考酚酯+泼尼松,后因移植肾肾病（4例）或并发肿瘤（1例）而将他克莫司（或环孢素A）转换为SRL。发生间质性肺炎时,临床表现为发热,伴有呼吸道症状以及呼吸困难,CT和胸片检查有阳性表现。结果 发生间质性肺炎后,4例5次停用SRL,另外3例减少SRL的用量,3～14 d后发热和呼吸道症状逐渐好转,2～4周后胸部影像学检查提示肺炎开始逐渐吸收,而病变完全吸收则需要2～6个月。结论 肾移植后使用SRL可继发间质性肺炎,一旦发生间质性肺炎,应立即减少SRL的用量或停用SRL。     

肾移植受者术后应用他克莫司发生耳神经毒性一例

肾移植受者术后应用他克莫司常见的神经毒性表现为肢体震颤和失眠等,而对其引起的耳神经毒性报道很少见.本院I例受者于肾移植术后4个月因环孢素A的肝毒性改用他克莫司引起耳神经毒性.报道如下.     

西罗莫司治疗心脏死亡器官捐献肾移植术后急性排斥反应(附1例报告并文献复习)

目的探讨西罗莫司在心脏死亡器官捐献(donation after cardiac death,DCD)肾移植术后急性排斥反应中的应用。方法回顾性分析1例接受同种异体DCD供肾受者肾移植术后发生急性排斥反应,早期应用西罗莫司治疗的临床资料并复习相关文献。结果 1例DCD供肾肾移植受者,采用他克莫司(FK506)+吗替麦考酚酯(MMF)+泼尼松三联抗排斥免疫方案(FK506每次3mg,每日2次;MMF每次750mg,每日2次;泼尼松每次15mg,每日1次),术后即出现无尿,诊断为移植物功能延迟恢复(DGF)。行血液透析治疗,每周3次。术后35d发现尿量减少,移植肾彩色多普勒超声提示急性排斥反应,经肾上腺皮质激素冲击治疗无效后,血清肌酐(Scr)升高,提示治疗无效,改为西罗莫司+FK506+MMF+泼尼松的四联方案(西罗莫司每次0.5mg,每日1次;FK506每次2mg,每日2次;MMF每次250mg,每日2次;泼尼松每次15mg,每日1次),并减少他克莫司剂量。改用方案后3d患者Scr逐渐下降至正常,至出院后未再出现排斥反应。患者随访至2013年4月移植肾功能稳定,生活质量良好。结论西罗莫司有利于DCD供肾肾移植患者肾功能早期恢复,对术后急性排斥反应有一定疗效。     

高度致敏受者肾移植的临床处理

目的 总结高度致敏受者肾移植的临床处理经验.方法 26例群体反应性抗体(PRA)峰值≥50%的高致敏患者行同种异体肾移植术.男8例,女18例.平均年龄(47.6±7.4)岁.首次接受移植者15例,二次移植者10例,三次移植者1例.亲属供肾1例,尸体供肾25例.术前要求交叉配型阴性.术后采用抗CDzs单克隆抗体诱导,他克莫司加吗替麦考酚酯加激素三联维持治疗.结果 18例移植后1周内血肌酐(SCr)降至正常.2例分别于术后第2、3天出现加速性排斥反应,经过血浆置换3次及抗CD3单克隆抗体5 mg/d治疗5 d后,1例3周后移植肾功能逐渐恢复正常,另1例排斥反应未能逆转,最终摘除移植肾.发生急性排斥反应6例,2例经激素冲击治疗后逆转,4例为耐激素排斥反应,经抗CD3单克隆抗体5 mg/d治疗5 d和血浆置换治疗3次后,排斥反应逆转.1年移植肾存活率96%(25/26).结论 高度致敏受者肾移植不仅需要HLA配型良好,并且要求供者HLA抗原避开受者所有预存的抗HLA抗体;术后采用抗CD25单克隆抗体诱导,他克莫司加吗替麦考酚酯加激素三联维持治疗,能有效预防和治疗急性排斥反应.     

Application of immune cell functional assay in monitoring immune status in renal transplant recipients

Objective To evaluate the value of immune cell functional assay (ImmuKnow CD4+ T cell ATP assay) in monitoring immune status in renal recipients. Methods A total of 131 adult renal transplant recipients who received transplantation for the first time were under investigation. According to the dynamic monitoring ATP concentration before operation, 2 week, 1, 3, 6 months after operation and during infect or rejection, samples were divided into the following groups: health control group (HC), pretransplant (Pre-Tx) group, stable (Tx) group, infect group, acute rejection (AR) group, acute kidney injury (AKI) group. Immune cell functions were detected by ImmuKnow CD4+ T cell ATP assay. Lymphocyte subsets (CD4+/CD8+) were analysed and serum concentrations of FK506 were tested. Mixed lymphocyte reaction(MLR) was analysed. Results The ATP concentration was no significant difference between Pre-Tx and HC group. The ATP concentration of 2 weeks, 1 months after operation were significantly higher than Pre-Tx group (P＜0.01). After 3 months, 6 months follow-up, the ATP concentration stabilized with time. The ATP concentration of AR group was significantly higher than other three groups (Tx, infect and AKI group, all P＜0.05). The correlation coefficient between the ATP concentration and MLR, CD4+/CD8+, FK506 level were R2＝0.0072, R2＝10-6, R2＝0.004 respectively (all P﹥0.05). Conclusions The cell-mediated immunity of recipients is relatively strongger during the first month after transplantation. The ATP concentration is not related to the levels of MLR, CD4+/ CD8+, FK506. ImmuKnow ATP assay is a valuable predictor in acute rejection diagnosis.     

Immune functional assay for immunosuppressive management in post‐transplant malignancy

Uemura T, Riley TR, Khan A, Hollenbeak C, Schreibman I, Ghahramani N, Reeves B, Domen RE, Zander DS, Kadry Z. Immune functional assay for immunosuppressive management in post‐transplant malignancy.
Clin Transplant 2011: 25: E32–E37. © 2010 John Wiley & Sons A/S. Abstract: Immunosuppression management in post‐transplant malignancy is challenging because of a lack of objective immunologic assessment tools. The ImmuKnow assay measures the ATP level from CD4 T cells, quantifying cell‐mediated immunity and providing an insight into the immune status of transplant recipients. Its potential use in patients with post‐transplant de novo malignancy was evaluated. Thirteen adult transplant patients with de novo malignancy were divided into survivors (n = 9) and non‐survivors (n = 4) after malignancy treatment. Tacrolimus and the ImmuKnow levels were monitored before, during, and after malignancy treatment. The ImmuKnow level in non‐survivors group was significantly lower before and after malignancy treatment compared to survivors group (p = 0.013 and 0.0014 respectively). In survivor group, the ImmuKnow level was significantly decreased during malignancy treatment (p = 0.019) but recovered to the initial level after the treatment. However, in non‐survivor group, the ImmuKnow level remained suppressed throughout the observed period despite a reduction in immunosuppressive drug levels. The ImmuKnow assay can be an objective means evaluating immune status of patients with de novo malignancy. The ImmuKnow assay can express the degree of immune suppression induced by chemotherapeutic or radiation therapy and may be a useful tool in optimizing the timing of re‐introduction of immunosuppression after malignancy treatment.     

肝移植术后ImmuKnow细胞免疫功能与白细胞及T淋巴细胞计数的相关性研究

目的 探讨肝移植术后ImmuKnow细胞免疫功能测定值与白细胞分类计数和T淋巴细胞亚群计数的相关性,为临床提供一种价格低廉快速判断肝移植受者细胞免疫功能的方法.方法 选择49例行经典原位肝移植术受者术后2周至2个月内在无糖皮质激素应用情况下的外周血样本.分析ImmuKnow测定值与白细胞分类计数和T淋巴细胞亚群计数的相关性.并随机选择5例无激素免疫抑制的移植受者于术后2、3、4、6、8周分别重复检测上述指标,进一步验证其相关性.结果 白细胞总数与ImmuKnow ATP值相关性最高,相关系数为0.821;中性粒细胞计数与ImmuKnow ATP值相关性次之,相关系数为0.787;单核细胞计数相关系数虽然有统计学意义,但相关系数低于0.5.淋巴细胞计数和淋巴细胞亚群计数与ImmuKnow ATP值的相关性无统计学意义.5例无激素免疫抑制受者术后重复检测ImmuKnow ATP值的变化与细胞总数的变化呈正相关,相关系数均>0.5.结论 肝移植术后早期白细胞计数与CD4+T细胞ImmuKnow ATP值具有一定的正相关性,白细胞计数的变化,可以在一定程度上反映ImmuKnow ATP值的变化.

Abstract：

Objective To explore the relationship between peripheral differential blood count and ATP value in Cell CD4 + T tested by ImmuKnow method in liver transplants. Methods In this study 49recipients after classic orthotopic liver transplantation (OLT) were enrolled. In a period from two weeks to two months after transplantation when all were free of glucocorticoid. Blood were sent for WBC differential samples count and ATP value in Cell-CD4 + T tested by ImmuKnow method via SPSS17. 0 software. Five more samples were selected randomly for duplicated testing of the indices in Week2, 3, 4,6 and 8 after the transplanting operation to further verify the relativity. Results White blood cell count has the highest relativity with ImmuKnow ATP value at 0. 821. The 5 recipients were repeatedly tested for ImmuKnow ATP values that were found positively correlated to cell count with a coefficient of over 0. 5. Conclusions The peripheral leukocyte count in early stage after liver transplantation is in positive correlation with ATP value in Cell CD4 + T, and the changes of numeration of leukocyte reflect changes of ATP value.     

雷公藤内酯醇在小鼠同种异体胰岛移植中的抗排斥作用

目的探讨雷公藤内酯醇（triptolide,TPT）在小鼠同种异体胰岛移植中的抗排斥作用及其机理。方法采用BALB/c小鼠作为供体,进行胰岛分离,以链脲佐菌素（streptozotocin,STZ）诱导的C57BL/6糖尿病小鼠作为受体,行左肾被膜下胰岛移植。将移植后糖尿病小鼠随机（随机数字表法）分为3组,每组8只。于胰岛移植术后前5 d分别给予腹腔注射1%吐温80溶剂（对照组）、TPT 50μg/kg（L-TPT组）和100μg/kg（H-TPT组）,之后隔天注射1次,至术后第14天结束。术后监测受体血糖水平变化;并于术后第10天每组随机（随机数字表法）选取3只小鼠,切取左侧肾脏行病理学检查,流式细胞术检测脾淋巴细胞中CD4＋CD25＋Foxp3＋调节性T细胞比例。结果对照组、L-TPT组和H-TPT组移植胰岛的中位存活时间分别为12.6 d（9～16 d）、21.4 d（14～27 d）和27.6 d（19～34 d）;脾淋巴细胞中CD4＋CD25＋Foxp3＋调节性T细胞比例分别为（5.2±0.6）%、（12.0±1.3）%和（15.7±1.8）%。与对照组相比,L-TPT组和H-TPT组小鼠移植胰岛的中位存活时间明显延长（P〈0.05）,CD4＋CD25＋Foxp3＋调节性T细胞比例显著增高（P〈0.05）。结论 TPT通过上调移植受体CD4＋CD25＋Foxp3＋调节性T细胞比例,减轻了胰岛移植后的排斥反应,显著延长了移植胰岛的存活时间,其免疫抑制作用呈剂量依赖性。     

Cylex ImmuKnow测定稳定肝移植患者CD4+T淋巴细胞活性临床分析

目的 探讨中国人肝移植术后肝功能稳定患者ImmuKnow免疫细胞功能测定与临床免疫抑制状况的相关性.方法 收集46例肝移植术后肝功能稳定患者的临床资料,选取性别、年龄、病因、血常规、肝功能、肾功能、乙肝五项和丙肝病毒载量、CD淋巴细胞亚群、他克莫司血药谷浓度、ImmuKnow值作为观察指标,对术后肝功能稳定患者ImmuKnow值与其他各相关临床指标进行多因素回归分析.结果 肝移植术后(22±15)个月肝功能稳定患者ImmuKnow值为(203±114)ATPng/ml(38.47～524.06 ATP ng/ml).回归分析显示ImmuKnow值与白细胞计数、CD3+淋巴细胞绝对计数以及CD3+CD4+T淋巴细胞绝对计数有相关性(P<0.05).ImmuKnow值与他克莫司谷值浓度、他克莫司日用量以及患者性别、年龄及其他肝功能指标没有相关性(P>0.05).5例合并活动性丙型肝炎病毒感染者有较低的ImmuKnow值(<61 ATP ng/ml).结论 Cylex ImmuKnow检测可以用于稳定肝移植患者免疫抑制的监恻,具有潜在的临床应用价值.综合评价肝移植患者免疫状态需要联合ImmuKnow、T淋巴细胞亚群、血药浓度、肝功能指标检测等相关检查,才能有效指导肝移植受体免疫抑制剂的个体化使用.

Abstract：

Objective To identify the level of functional immunity as measured by the ImmuKnow assay in Chinese stable liver transplant recipients and to correlate these values with the dose and the trough levels of immunosuppressant, and with other clinical parameters of these patients. Methods Functional immune response was assessed by the ImmuKnow assay in 46 blood samples taken from 46 stable liver transplant recipients from Beijing Youan Hospital, Capital Medical University Liver Transplantation Center. Results The average ATP value in these stable liver transplant recipients was 203±114 ng/ml (range: 38.47 ATP ng/ml to 524.06 ATP ng/ml) at 22± 15 month post liver transplantation. There was no correlation either between ImmuKnow ATP values and the tacrolimus trough levels, or between ImmuKnow ATP values and the liver function (P<0. 05). Stepwise multiple regression analysis identified WBC and CD3+, CD3+ CD4+ as independent predictors of ImmuKnow assay levels when age, gender and underlying diagnosis were taken into account (P<0. 05). Five patients who were detected to have active HCV infection had lower ImmuKnow ATP values (<61 ng/ml). Conclusions The Cylex ImmuKnow assay ATP values were lower in Chinese stable liver transplant recipients compared with American patients. Further investigation is required to determine the role of the ImmuKnow assay in tailoring immunosuppressant therapy in liver transplant recipients.     

非糖皮质激素的免疫抑制方案对同种异体移植胰岛的保护作用

目的　评价非糖皮质激素的免疫抑制方案对防止大鼠同种异体胰岛移植排斥反应的效果。方法　大鼠同种异体胰岛移植后 ,分别应用他克莫司 (FK5 0 6 ) 霉酚酸酯 (MMF)和FK5 0 6 MMF 泼尼松 (Pred)行免疫抑制治疗两周 ,并设对照组 ,动态观察受者血糖、胰岛素及C肽变化 ,并作移植部位的形态学检测。结果　FK5 0 6 MMF组和FK5 0 6 MMF Pred组与对照组相比 ,移植胰岛存活时间明显延长 ,移植后 2个月在受者肝汇管区可见较多形态完整的胰岛细胞。FK5 0 6 MMF组维持术后正常血糖、胰岛素及C肽的时间超过 6 0d ,而FK5 0 6 MMF Pred组与前者比较 ,分泌C肽较少 (P <0 .0 5 ) ,血糖维持在较高水平 (P <0 .0 1) ,胰岛素水平两组差异无显著性。FK5 0 6 MMF Pred组停药两周以后的血糖水平较用药期间、停药两周内有明显降低 (P <0 .0 5 ) ,胰岛素和C肽分泌有所增多 ,但差异无显著性。结论　应用FK5 0 6 MMF和FK5 0 6 MMF Pred均有很强的免疫抑制效应 ,但糖皮质激素对胰岛细胞有毒性作用。小剂量FK5 0 6与MMF联用对移植胰岛细胞有较强的保护作用。     

他克莫司对肝移植受者外周血T淋巴细胞亚群及共刺激分子表达的影响

目的 探讨他克莫司（FK506）对肝移植受者外周血T淋巴细胞亚群及其表面共刺激分子表达的影响。方法 采用荧光标记单克隆抗体和流式细胞技术，测定术后采用FK506治疗的肝移植受者（FK506治疗组）在用FK506后1、2、3、4周时的外周血T淋巴细胞亚群及其表面共刺激分子CD28、CD152和ICOS分子的表达情况，以健康志愿者（健康对照组）和患终末期肝脏疾病拟行肝移植者（肝病对照组）为对照。结果 CD3^＋T淋巴细胞在各组间的差异均无统计学意义（P〉0．05）。经FK506治疗后，肝移植患者的CD4^＋T淋巴细胞逐渐减少，CD8^＋T淋巴细胞逐渐增加，并恢复至健康对照组水平（P〉0．05）。FK506治疗组T淋巴细胞亚群表面CD28分子和ICOS分子表达逐渐下降，并明显低于健康对照组（P〈0．05），而CD152分子表达增加，且明显高于健康对照组（P〈0．05）；其ICOS分子表达水平的下降晚于CD28分子，CD4^＋CD28^＋T淋巴细胞、CD8^＋CD28^＋T淋巴细胞和CD4^＋ICOS^＋T淋巴细胞均呈现相近的变化规律。结论 FK506能迅速纠正移植受者T淋巴细胞亚群紊乱，并抑制正性共刺激分子CD28和ICOS的表达，促进负性共刺激分子CD152的表达。     

The effects of immunosuppressive drugs on the regulation of activation-induced apoptotic cell death in thymocytes.

This study investigated the effects of immunosuppressive drugs on the regulation of thymocyte sensitivity to clonal deletion via programmed cell death, or apoptosis. We have previously shown that TcR/CD3 cross-linking and intracellular stimuli that mimic TcR/CD3 cross-linking induce apoptosis in many immature thymocytes in the presence, but not in the absence, of cyclosporine (CsA). We have interpreted those results to suggest that TcR/CD3-associated signals induce a CsA-sensitive mechanism that protects the cells from activation-induced apoptosis. In the present study, we compared the effects of CsA, FK506, and rapamycin (RAP) on the regulation of thymocyte apoptosis. Optimal concentrations of CsA and FK506 augmented apoptosis to similar levels. However, FK506 was approximately 100-fold more potent than CsA in thymocytes, which parallels the relative potencies of these drugs in inhibiting mitogen-induced proliferation of mature T cells. In contrast to CsA and FK506, RAP did not exhibit substantial apoptosis-augmenting activity. However, RAP interfered with the activity of FK506. This pattern mirrors that of RAP in TcR/CD3-mediated signaling pathways in mature T cells. Together these results provide evidence (1) that CsA, FK506, and RAP can act on immature thymocytes, (2) that the mechanisms by which the drugs affect mature and immature T cell responses are similar, and (3) that immunosuppressive drug therapy may affect not only mature peripheral T cells but also developing immature thymic T cells.     

FK 506 reverses acute graft-versus-host disease after allogeneic bone marrow transplantation in rats.

Severe graft-versus-host disease was induced by transplantation of ACI rat bone marrow and spleen cells into irradiated Lewis rat recipients. Treatment with FK 506 or cyclosporine A (CsA) was started after clinical and histologic evidence of acute GVHD was present. A 14-day course of FK 506 at 1.0 mg/kg/day could rescue 100% of the animals suffering from GVHD. In contrast only one half of the animals treated with CsA at a high dose of 25 mg/kg/day recovered. After cessation of immunosuppressive therapy, FK 506-treated animals displayed a marked prolonged disease-free interval as compared to CsA-treated bone marrow recipients. Recurrence of the disease in these animals could be prevented when FK 506 treatment was continued after the induction period with a low maintenance dose of 0.1 mg/kg/day every other day.