他克莫司与环孢菌素A对肝移植受者CD4/CD8 T淋巴细胞亚群及共刺激分子的调节作用

目的:探讨他克莫司(Tacrolimus, FK506)与环孢菌素A(CsA)对肝移植受者T淋巴细胞亚群共刺激分子的调节作用.方法:采用荧光标记单克隆抗体(mAb)结合流式细胞技术, 测定移植术后使用FK506或CsA治疗2月末的肝移植受者外周血T细胞亚群及其表面共刺激分子CD28、CD152 和ICOS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进行肝移植者(疾病对照组)为对照.结果:疾病对照组T细胞亚群平衡紊乱、共刺激分子表达异常(P＜0.05).治疗组肝移植受者T淋巴细胞亚群表达恢复至健康对照水平, T细胞表面CD28和ICOS分子表达显著降低(P＜0.05)而CD152分子表达明显升高(P＜0.05).比较不同药物治疗组:CsA治疗组CD4 T细胞表达和CD8 T细胞表面CD28、CD152分子表达均明显高于FK506治疗组(P＜0.05);其他指标无统计学意义(P＞0.05).结论:在常规血药浓度条件下FK506和CsA的对CD4/CD8T细胞亚群及共刺激分子的免疫调节作用存在差异.FK506对T细胞亚群的调节作用强于CsA.FK506可同时抑制正性共刺激分子CD28和ICOS表达并促进负性共刺激分子CD152表达, 而CsA对T细胞免疫抑制作用主要是通过促进CD152分子的高表达介导.     

FK506对肝移植受者T细胞亚群上CD152和PD-1的调节研究

目的:动态观察肝移植受者外周血T细胞表面CTLA-4/CD152和PD-1的表达,探讨FK506对负性协同刺激分子的调节作用.方法:采用酶增强免疫分析法测定FK506的血药浓度.外周血T细胞亚群和T细胞表面CD152和PD-1分子的表达利用流式细胞术(FCM)进行检测.结果:各时间组间FK506血药浓度无统计学意义(P＞0.05).随治疗时间延长,CD4 T细胞持续下降,至治疗3月时已明显低于健康对照组(P＜0.05).而各治疗组CD4 T细胞百分率均明显低于疾病对照组(P＜0.05).各时段治疗组CD8 T细胞均明显高于疾病对照组(P＜0.05).肝移植术后,CD4 和CD8 T细胞上CD152的表达较健康对照组升高(P＜0.05),治疗2周和1月组还高于疾病对照组(P＜0.05).治疗2月和3月组CD4 CD152 T细胞的表达较治疗2周和1月组下降(P＜0.05).治疗3月组CD8 CD152 T细胞的表达较治疗2周和1月组降低(P＜0.05).术后T细胞亚群上PD-1的表达有升高趋势.CD4 T细胞上PD-1的表达在治疗2周开始明显高于健康对照组(P＜0.05).CD8 T细胞上PD-1的表达从治疗1月时明显高于疾病对照组(P＜0.05).结论:FK506能上调T细胞表面负性协同刺激分子CD152和PD-1的表达,可能参与抑制效应T细胞的过度增殖与活化,维持移植受者的存活和免疫稳态.     

MDR1基因多态性对肝移植受体普乐可复治疗的影响

目的探讨普乐可复（Tacrolimus，FK506）服用剂量和血药浓度的个体差异与供受体多药耐药基因1（multidrug resistance gene 1，MDR1）多态性的关系。方法监测50例口服普乐可复的肝移植受体体重、服药剂量、全血谷浓度，用PCR-限制性片段长度多态性分析的方法检测供受体MDR1第3435位C／T基因型，计算每日每公斤体重的FK506用量和血药浓度与每日每公斤体重的FX505用量的比值，并分析与供受体MDR1基因型的关系。结果在各50例供受体研究中，23％为MDR1 CC基因型，54％为CT基因型，13％为TT基因型。MDR1 CC基因型受体的每日每公斤体重的FK506用量明显高于CT和TT基因型受体，前者血药浓度与每日每公斤体重的FK506用量的比值显著低于后两者，供体MDR1基因型对此无明显影响。结论普乐可复服用剂量和血药浓度与受体的MDR1第3435位点基因多态性相关。MDRI多态性分析可指导肝移植受体普乐可复临床用药的个体化。     

他克莫司与环孢菌素A对肝移植受者CD8+CD28-调节性T细胞的不同调节特性

目的 探讨他克莫司(FK506)与环孢菌素A(CsA)对肝移植受者CD8 GD28-调节性T细胞(Treg)及细胞因子IL-10的调节效应.方法 采用荧光标记单克隆抗体结合流式细胞技术分析接受FK506或CsA治疗的肝移植受者外周血CD8 T细胞及共刺激分子CD28的表达情况,采用流式细胞小球微阵列术(CBA)分析血浆中IL-10浓度.以健康志愿者和患终末期肝脏疾病拟进行肝移植者作为对照.结果 疾病对照组CD8 T细胞和CD8 CD28-T细胞/CD8 CD28 T细胞比值(Ratio值)显著低于健康对照组(P＜0.05).FKS06治疗组CD8 T细胞表达显著回升(P＜0.05),且增加的CD8 T细胞主要为CD8 CD28-Treg(P＜0.05).CaA治疗组CD8 T细胞和CD8 CD28-Treg未出现明显回升(P＞0.05).且FKS06治疗组CD8 CD28-Tteg表达显著高于CaA治疗组(P＜0.05).两治疗组血浆IL-10水平均显著高于健康对照组和疾病对照组(P＜0.05),但组间差别无显著性(P＞0.05).结论 FKS06可促进肝移植受者外周血CD8 CIY28-Treg表达并同时促进IL-10的产生从而加强T细胞的免疫耐受,而CaA虽不能有效促进CD8 CD28-Treg的表达但却能促进IL-10的产生.     

肝移植后受者淋巴细胞亚群表达与免疫平衡

背景:有文献报道,肝移植后受者外周血淋巴细胞的变化较肝脏酶学的改变更为敏感,其特异性有待进一步研究。目的:分析淋巴细胞亚群中CD3-/HLA-DR+,CD3+/CD25+和CD3+/HLA-DR-与肝移植受者机体免疫状况和并发症的关系。方法:应用全自动生化分析仪和流式细胞分析仪检测56例肝移植受者移植后肝功能和淋巴细胞亚群,依照肝功能情况划分为肝功能正常组52例和肝功能异常组27例,肝功能异常组中分为急性排斥组7例、药物反应组11例和原因不明组9例。分析各组肝移植受者CD3-/HLA-DR+,CD3+/CD25+和CD3+/HLA-DR-表达水平与其并发症的关系。结果与结论:肝功能正常组CD3-/HLA-DR+和CD3+/CD25+的表达水平低于肝功能异常组(P=0.011,0.002),CD3+/HLA-DR-的表达高于肝功能异常组(P=0.012)。CD3-/HLA-DR+和CD3+/CD25+在急性排斥组的表达水平明显高于药物反应组(P=0.039,0.048),急性排斥组CD3+/HLA-DR-的表达水平低于药物反应组(P=0.007)。提示CD3-/HLA-DR+,CD3+/CD25+和CD3+/HLA-DR-的表达水平与肝移植后受者机体免疫状况及并发症密切相关,可作为判断肝移植后受者并发症的辅助指标以及进行免疫干预的参考依据。     

发光酶免疫分析法测定环孢霉素血药浓度

建立发光酶免疫分析(LEIA)方法进行环孢霉素(Cyclosporine)治疗药物监测(TOM).用定标、质控、回收率、精密度、抗干扰等对LEIA进行评价,并对用药达稳态浓度后肾移植患者的肝素抗凝全血中的环孢霉素血药浓度进行测定.结果表明:定标、质控均符合实验要求,平均回收率为99.6%,CV为2.1%,高胆红素、血红蛋白、甘油三酯以及高、低总蛋白等对LEIA的干扰误差均<10%.肾移植患者无药物中毒反应和排斥反应,环孢霉素血药浓度平均值为190.3μg/L.LEIA法测定环孢霉素血药浓度具有较高的特异性和稳定性.     

FK506作为佐剂刺激Tfh细胞增强体液免疫水平的研究

目的:探讨他克莫司(FK506)作为佐剂通过刺激Tfh细胞增强疫苗体液免疫水平的机制。方法:利用FK506与模式蛋白(卵清白蛋白,OVA)皮下注射免疫BALB/c小鼠,免疫三次,利用ELISA方法检测抗体水平;利用抗体染色流式细胞仪检测Tfh细胞、B细胞表面分子IL-21R及记忆性B细胞标志分子CD27表达。结果:FK506作为OVA蛋白佐剂,能够显著提高小鼠OVA特异性的IgG水平,增强体液免疫水平;免疫后的小鼠Tfh细胞表达IL-21水平显著高于其他对照组。同时,B细胞表达IL-21R及记忆性B细胞标志分子CD27显著高于其他对照组。表明FK506作为佐剂刺激Tfh细胞表达IL-21,作用于B细胞增强抗体水平。结论:FK506能够作为蛋白疫苗佐剂刺激Tfh细胞表达IL-21;IL-21可能通过与B细胞表面IL-21R作用,增强抗体的分泌;并刺激记忆性B细胞的产生,进而增强体液免疫水平。     

ABCB1基因多态性对肝移植后他克莫司用量的影响

背景：钙神经素抑制剂他克莫司被广泛用于移植后预防排斥反应的发生,但其治疗窗狭窄,且药代动力学个体差异较大。 目的：观察ABCB1基因多态性对肝移植患者移植后早期免疫抑制剂他克莫司的用量及C/D比值的影响。 方法：选择2008-01/2010-09-31在昆明市第一人民医院暨昆明医学院附属甘美医院肝胆外科接受原位肝移植患者67例,通过检测67例肝移植受者移植后不同时间他克莫司的血药浓度及其用量,并利用DNA直接测序检测受体ABCB1的基因多态性,分析肝移植后免疫抑制剂他克莫司的用量及其血药浓度与ABCB1基因多态性的关系。 结果与结论：肝移植后他克莫司的口服需药量在个体间存在很大差异,67例肝移植患者中,ABCB1不同位点的基因多态性分布不同,其中仅ABCB1 3435C>T基因多态性与他克莫司用量有关。提示ABCB1的基因多态性可能是患者肝移植后他克莫司药代动力学显著个体差异的重要因素,ABCB1 3435C>T野生型的患者需要更高剂量的他克莫司便可达到目标血药浓度水平,检测ABCB1的基因多态性可以优化肝移植后免疫抑制剂的个体化治疗方案。     

丙氨酰-谷氨酰胺下调口服他克莫司损伤的肠黏膜组织中iNOS和TNF-α的表达

目的： 研究丙氨酰-谷氨酰胺(Ala-Gln)对口服FK506损伤的肠黏膜组织中iNOS和TNF-α分子表达的影响。 方法： BALB/c小鼠24只，随机分成对照组、FK506低剂量组、FK506高剂量组及Ala-Gln治疗组，分别给以0.2 mL生理盐水、FK506 0.1 mg/kg、1.0 mg/kg灌胃和FK506 1.0 mg/kg灌胃及丙氨酰-谷氨酰胺 0.5 g/kg腹腔注射。隔天给药，6周后采集回肠标本。HE染色和扫描电镜观察肠黏膜组织形态学改变；FITC-dextran(FD4)检测肠黏膜通透性；RT-PCR检测小肠黏膜iNOS和TNF-α mRNA的表达情况；Western blotting检测iNOS和TNF-α蛋白表达水平。结果： FK506高剂量组的肠黏膜对FD4的通透性明显增加，扫描电镜示小肠绒毛破坏明显，而Ala-Gln治疗组小肠绒毛破坏减轻，对FD4的通透性下降；FK506高剂量组小肠黏膜iNOS mRNA和TNF-α mRNA表达增强，而Ala-Gln治疗组表达则明显下调；iNOS和TNF-α蛋白表达水平的变化与此一致。结论： FK506通过上调iNOS和TNF-α的表达对小肠黏膜产生损伤，使小肠壁的通透性增加。Ala-Gln对FK506所致的肠黏膜屏障功能损伤具有保护作用，该作用可能与下调iNOS和TNF-α的表达有关。     

普乐可复防治大鼠抗肾小球基底膜肾炎的实验研究

目的:观察普乐可复(FK506)防治大鼠抗肾小球基底膜(GBM)肾炎的疗效。方法:复制大鼠抗GBM肾炎模型。实验分3组:肾炎+FK506组、肾炎对照组及正常对照组。大鼠一次性尾静脉注射抗GBM抗血清后6 h内皮下注射FK506注射液(0.5 mg·kg^-1·d^-1), 至第21 d。对照组则给予等量的生理盐水。定期于第4 d、第14 d和第21 d, 检测大鼠尿蛋白、血清肌酐和尿素氮水平, 观察肾组织病理学改变, 以及检测T淋巴细胞转化功能。结果:肾炎对照组大鼠注射抗血清后于第4d即出现异常蛋白尿, 血清肌酐和尿素氮亦持续上升;肾小球内可见细胞数增加和新月体形成, 肾小管内大量蛋白管型, GBM呈不规则增厚, 足突大片融合;T淋巴细胞转化功能异常。而肾炎+FK506组大鼠上述病变均明显较轻。结论:FK506能够明显改善大鼠抗GBM肾炎的肾功能。     

肝移植后他克莫司血药浓度对外周血单个核细胞内HBV DNA的影响

背景：肝移植后他克莫司等免疫抑制剂的长期应用导致机体细胞免疫功能降低,并有可能影响机体对乙肝病毒的清除。 目的：分析乙肝相关肝移植患者后不同浓度他克莫司对外周血单个核细胞中的HBV DNA含量的影响。 方法：纳入乙肝相关终末期肝病肝移植受者23例,根据移植后12周清晨空腹他克莫司血药浓度,分为高浓度组(≥ 10 μg/L) 9例和低浓度组(< 10 μg/L)14例,同时用荧光标记单克隆抗体结合流式细胞技术检测外周血T细胞亚群的百分比,用实时荧光定量PCR检测外周血单个核细胞内的HBV DNA。 结果与结论：用多元线性回归分析外周血单个核细胞内的HBV DNA含量与CD8⁺CD152⁺呈正相关,与CD8⁺CD28⁺呈负相关。高血药浓度他克莫司的患者外周血单个核细胞内的HBV DNA高于低浓度组,其改变与反映细胞免疫功能的指标CD8⁺CD152⁺和CD8⁺CD28⁺的变化有关。     

他克莫司在体外对HepG2.2.15细胞增殖及乙型肝炎病毒复制的影响

背景：肝癌复发与乙肝病毒再感染两者关系尚不明确,有人认为与肝移植后免疫抑制剂应用有关。 目的：观察他克莫司在体外对肝癌HepG2.2.15细胞增殖及对细胞内乙肝病毒复制的影响。 方法：选择肝癌HepG2.2.15细胞进行体外培养,第3代细胞培养24 h后加他克莫司进行干预,0 g/L他克莫司作为对照组,50 g/L 他克莫司为低浓度组,100,500 g/L他克莫司为中浓度组,1 000,3 000 g/L他克莫司为高浓度组。 结果与结论：①中、高浓度的他克莫司对HepG2.2.15细胞有增殖抑制作用,低浓度无抑制作用,且有相关性。②高浓度他克莫司作用时使HepG2.2.15细胞停止在G0/G1期。③他克莫司可以使HepG2.2.15细胞中CyclinA表达降低,且呈浓度依赖性,他克莫司浓度越高,CyclinA表达越少。④他克莫司作用HepG2.2.15细胞,对HBV的复制无影响。结果说明他克莫司在体外对HepG2.2.15增殖有抑制作用,其中CyclinA可能发挥一定的作用,而对乙肝病毒复制没有影响。     

药物基因组学影响肾移植术后他克莫司疗效的研究进展

他克莫司(tacrolimus,FK506)是从链霉菌属中分离出来的钙调磷酸酶抑制剂,是用于预防器官移植排斥反应的一线免疫抑制剂.他克莫司作为免疫抑制剂,具有良好的治疗效果.然而,其治疗窗狭窄和药动学个体差异巨大,容易导致免疫抑制不足或过度抑制而诱导肾毒性、糖尿病等不良反应,目前是困扰临床实践的关键问题.     

Autoantibodies against cytochrome P450s in sera of children treated with immunosuppressive drugs

Treatment with the immunosuppressive drugs cyclosporin and tacrolimus, the mainstays of anti-graft rejection and autoimmune disease therapy, is limited by their hepato- and nephrotoxicity. The metabolic conversion of these compounds to more easily excretable products is catalysed mainly by hepatic cytochrome P4503A4 (CYP3A4) but also involves extrahepatic CYP3A5 and other P450 forms. We set out to study whether or not exposure to cyclosporin and FK506 in children undergoing organ transplantation leads to formation of autoantibodies against P450s. Immunoblotting analysis revealed anti-CYP reactivity in 16% of children on CyA for anti-graft rejection or treatment of nephrosis (n = 67), 31% of kidney transplant patients switched from CyA to FK506 (n = 16), and 21% of kidney and or liver transplant patients on FK506 (n = 14). In contrast, the frequency of reactive immunoblots was only 8.5% among the normal paediatric controls (n = 25) and 7% among adult kidney transplant patients on CyA or FK506 (n = 30). The CYP2C9+ sera were able to immunoprecipitate in vitro translated CYP2C9 and the immunoblot reactivity showed striking correlation to peaks in the age at onset of drug exposure. Sera were isoform selective as evidenced from Western blotting using human liver microsomes and heterologously expressed human P450s. These findings suggest that anti-cytochrome P450 autoantibodies, identified on the basis of their specific binding in immunoblots, are significantly increased among children on immunosuppressive drugs and in some cases are associated with drug toxicity and organ rejection.     

Effects of tacrolimus (FK506) and mycophenolate mofetil (MMF) on regulatory T cells and co-inhibitory receptors in the peripheral blood of human liver allograft patients

Context: Recent studies have shown that a combination treatment of mycophenolate mofetil (MMF) and tacrolimus (FK506) may be an option for organ transplantation patients.

Objective: In this study, we detected the effects of FK506 and MMF on the expressions of regulatory T cells (Tregs) and co-inhibitory receptors on Tregs in peripheral blood mononuclear cells (PBMC) of patients with stable phase after liver transplantation.

Materials and methods: A total of 35 patients with stable stage after 6?months of liver transplantation were divided into two groups including 20 patients were treated with FK506 monotherapy (FK506 group), and 15 patients with FK506 and MMF combination (FK506?+?MMF group). 15 healthy subjects were served as the control.

Results: It is found that percentages of CD3⁺, CD3⁺CD4⁺ and CD3⁺CD8⁺ T cells in FK506 group are lowered compared to the control group but they are elevated in FK506?+?MMF group. Amount of CD4⁺CD25⁺CD127low/-Treg cells in CD3⁺ CD4⁺T cells in FK506?+?MMF group was higher than that in FK506 group and control group. The expressions of co-inhibitory receptors (CTLA-4, PD-1, Tim-3, LAG-3 and TIGIT) on Tregs in FK506?+?MMF group were significant higher than those in the FK506 group and control group. The levels of the relative cytokines (TGF-β and IL-10) in FK506 group are down-regulated compared to the control group.

Conclusion: The application of FK506 combined with MMF may be superior to FK506 monotherapy for the patients to further induce the immune tolerance after liver transplantation.     

A retrospective analysis of the safety and efficacy of low dose tacrolimus (FK506) for living donor liver transplant recipients

We sought to evaluate the efficacy and effects of low-dose tacrolimus (FK506) to recipients with living donor liver transplantation (LDLT). A total of 66 patients who underwent LDLT between 2001 and 2007 were enrolled in this study. According to different doses of tacrolimus, the recipients were randomly divided into two groups: the low-dose tacrolimus group (group A) and the normal-dose tacrolimus group (group B). The blood concentration of tacrolimus and its side effects including infection, hyperglycemia, hypertension, high blood creatinine and jaundice were monitored once a week at the perioperative period, and once a month thereafter. Besides, the survival rates of the recipients were analyzed at the 1- and 3-year time point after operation. Among these patients, no significant acute rejection was detected after LDLT. The incidences of infection, hyperglycemia, liver dysfunction and renal impairment in group A were markedly lower than those in group B. However, no significant differences were detected in the incidence of hypertension between the two groups. Moreover, the recipients in each group had a similar survival rate according to the results of 1- and 3-year follow-up. The incidence of side effects that associated with tacrolimus positively correlated with tacrolimus blood concentration. In conclusion, long-term and low-dose administration of tacrolimus is a safe and effective treatment for LDLT recipients.     

Clinical efficacy of the Abbott Tacrolimus II assay for the IMx.

Monitoring tacrolimus is essential to maintain therapeutic concentrations. Performance of the new Abbott Tacrolimus assay (FK II) was evaluated and compared to the original tacrolimus assay (FK I). 189 trough whole blood samples from transplant cases were included in the study. Samples (n = 117) with FK I concentrations > 5 ng/mL were reanalyzed with the FK II assay. Patient samples (n = 43) that had FK I concentration < 5 ng/mL with apparent mean and range of 3.1 ng/mL and 0.7 to 4.5 ng/mL, respectively, were also reanalyzed with FK II to yield a mean of 5.9 ng/mL with a range of 2.9 to 10.8 ng/mL. Checking for patient compliance, samples (n = 10) with a FK I concentration of 0 ng/mL were re-analyzed. With one exception of a mislabeled cyclosporine sample, all samples (n = 9) showed FK506 levels greater than 2 ng/mL with the FK II assay. The FK II assay was shown to be a clinically efficacious assay, with improved sensitivity and acceptable precision versus the previous FK I assay.     

FK506 aerosol locally inhibits antigen-induced airway inflammation in Guinea pigs

BACKGROUND: Eosinophilic airway inflammation is a common pathological feature of asthma. It has been shown that FK506 given systemically suppresses antigen-induced airway inflammation in animal models. However, it is unknown whether inhaled FK506 can suppress the airway allergic inflammation/immune response and whether it acts locally or systemically. METHODS: We tested the effects of oral FK506 and inhaled FK506 on antigen-induced airway inflammation in guinea pigs. The tissue and blood concentrations of FK506 given via both routes were compared. The effect of inhaled FK506 on the expression of cytokine mRNA in lung and bronchoalveolar lavage fluid (BALF) cells was also tested. RESULTS: Both routes of administration of FK506 suppressed the airway eosinophilia in egg albumin (EA)-sensitized and -challenged animals. The effect of three inhaled puffs was almost equal to that of 1 mg/kg administered by the oral route. Following inhalation of three puffs, FK506 concentration in blood (AUC(0-24 h)) was approximately 1/21 of that following oral FK506 (1 mg/kg). After EA challenge, mRNA expression of interleukin (IL)-5, eotaxin and IL-1beta in BALF cells and IL-5 in the lung increased significantly. FK506 aerosol markedly inhibited IL-5 mRNA expression in the lung. In situ hybridization indicated that in the BALF IL-5 mRNA expression by lymphocyte-like cells was inhibited by FK506 aerosol. In addition, anti-IL-5 antibody injected intratracheally almost completely abolished eosinophilia in this model. CONCLUSION: Inhaled FK506 can suppress airway inflammation in guinea pigs, where the local action, presumably the inhibition of T-cell activation/function in the lung and airways, was primarily important.     

A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients.

Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.     

FK506 vs. cyclosporin. Pathologic findings in 1067 endomyocardial biopsies.

INTRODUCTION: Whether FK506 or cyclosporin is better for chronic immunosuppression in heart transplant patients has been debated. We examined endomyocardial biopsies from patients treated with these two drugs to determine if there was a difference in frequency of histologic cellular rejection episodes and Quilty lesions. The Quilty lesion (AKA cyclosporin effect) may be an atypical form of rejection, and is thought to be related to the use of cyclosporin immunosuppression. METHODS: We reviewed 1067 endomyocardial biopsies from 65 patients who were assigned FK506 or cyclosporin after heart transplantation. RESULTS: The number of episodes of rejection (162 FK506 vs. 145 cyclosporin) was the same. However, when compared to cyclosporin treatment, FK506 was associated with significantly more Quilty A lesions and fewer Quilty B lesions. CONCLUSION: FK506 appears to prevent some Quilty A lesions from progressing to Quilty B lesions. Since Quilty B lesion is associated with myocyte injury and Quilty A is not, this effect of FK506 could be associated with improved long-term graft function.