肾移植免疫诱导方案临床应用进展

随着免疫抑制剂的发展和免疫抑制方案的优化,肾移植受者和移植物的存活率显著提高,术后急性排斥反应发生率和移植物功能延迟恢复发生率也明显降低。但是标准的三联免疫抑制方案(钙调磷酸酶抑制剂+抗代谢药物+糖皮质激素)仍无法有效控制移植肾排斥反应,因此提出在移植前进行免疫诱导方案。免疫诱导治疗可推迟钙调磷酸酶抑制剂的应用时间,降低其使用剂量,减少术后短期急性排斥反应的发生,改善受者中远期预后。本文将从单克隆抗体为主的免疫诱导方案、多克隆抗体为主的免疫诱导方案以及间充质干细胞为主的免疫诱导方案进行探讨,以期为优化肾移植选择免疫诱导方案提供参考。     

个体化免疫诱导方案在肾移植中的应用进展

肾移植术后早期急性排斥反应发生的风险较高,严重影响受者的生存质量。2009年,改善全球肾脏病预后组织(KDIGO)建议将免疫诱导药物纳入肾移植术前免疫诱导方案中,其目的就是针对这一关键时期提供一定强度的免疫抑制,从而有效减少术后急性排斥反应的发生。目前全球各移植中心对于免疫诱导药物的选择及其有效性、安全性仍不确定。本文通过汲取国内外学者的研究成果,对比分析单克隆抗体包括白细胞介素-2受体拮抗剂、阿伦单抗、利妥昔单抗及多克隆抗体抗胸腺细胞球蛋白在肾移植术前免疫诱导中的应用效果,旨在为推动肾移植免疫诱导药物的个体化选择,提高受者的生存质量提供参考。     

ATG-F与OKT3在肾移植术后急性排斥反应中的应用研究

目的 探讨应用注射用兔抗人T淋巴细胞多克隆抗体(ATG-F)及注射用抗人T细胞CD3鼠单克隆抗体(OKT3)治疗肾移植术后急性排斥反应的效果、安全性和副反应等.方法 本中心施行同种异体肾移植术后对于激素冲击治疗不敏感的急性排斥患者51例,分为两组,分别给予多克隆抗体ATG-F和单克隆抗体OKT3治疗,并对治疗效果、安全性和药物的副反应等进行统计学分析.结果 ATG-F治疗28例,排斥逆转26例,治愈率89.3％;OKT3抗组23例,排斥逆转16例,治愈率69.6％.两组结果间有显著性差异(P＜0.05).结论 OKT3和ATG-F同为抗淋巴细胞的抗体,但其针对难治性急性排斥反应的治疗效果,存在明显差异.ATG-F临床效果肯定,并且用量灵活,副作用小.OKT3治疗效果一般,则具有术后感染发生率增加、白细胞减少等并发症.     

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.     

鼠抗人CD3、CD4单克隆抗体治疗肾移植后急性排斥反应的疗效观察

目的　探讨鼠抗人单克隆抗体预防及治疗尸肾移植后排斥反应的效果。方法　总结和分析了６２ 例肾移植后应用鼠抗人单克隆抗体ＷｕＴ３ 、ＷｕＴ４ 预防及治疗排斥反应的效果、单克隆抗体治疗期间血清游离单克隆抗体水平与受者抗鼠抗体的产生等情况。结果　该抗体对急性排斥反应的总体治愈率为７６ ．１ ％ , 对耐激素的难治性排斥反应的逆转率达６０ ．７ ％ ; ＣＤ３ 和ＣＤ４ 的抑制效应与血清游离单克隆抗体浓度密切相关; 首次应用单克隆抗体治疗时, 抗体的产生与否及量的多少并不影响疗效; 在单克隆抗体治疗的过程中, ＣＤ４／ＣＤ８ 下降明显者, 排斥逆转的可能性大; 停止治疗后Ｔ 淋巴细胞亚群未恢复正常水平者, 感染率明显上升。结论　ＷｕＴ３ 、ＷｕＴ４ 对肾移植后急性排斥反应, 包括耐激素急性排斥反应具有较为满意的治疗效果。     

肾移植免疫诱导治疗

肾移植早期机体对移植物反应强烈,移植肾功能延迟恢复、急性排斥反应等发生率高。采用淋巴细胞多克隆抗体或单克隆抗体等生物制剂进行的免疫诱导治疗可以有效的预防排斥反应发生,延长移植物的存活时间。本文对肾移植免疫诱导治疗的有关内容做一综述。     

肾移植免疫诱导治疗

肾移植早期机体对移植物反应强烈，移植肾功能延迟恢复、急性排斥反应等发生率高。采用淋巴细胞多克隆抗体或单克隆抗体等生物制剂进行的免疫诱导治疗可以有效的预防排斥反应发生，延长移植物的存活时间。本文对肾移植免疫诱导治疗的有关内容做一综述。     

监测肾移植受者外周血淋巴细胞选凝素-L表达的临床意义

目的　探讨肾移植前后外周血淋巴细胞选凝素 L的表达水平变化与肾移植排斥反应的关系。　方法　应用单克隆抗体 流式细胞仪荧光抗体技术监测 33例肾移植受者外周血淋巴细胞选凝素 L的表达水平。　结果　肾移植术后所有患者选凝素 L表达水平较术前显著降低 ,排斥反应时排斥组明显升高 (49.1± 13.8) ,同期稳定组无明显变化 (36 .5± 12 7)。　结论　选凝素 L与肾移植排斥反应密切相关 ,抑制选凝素 L表达是联合应用免疫抑制剂防治排斥反应的重要作用机制 ,监测选凝素 L的表达水平有助于肾移植排斥反应的诊断。     

鼠抗人CD3,CD4单克隆抗体治疗肾移植后急性排斥反应的疗？…

目的 探讨鼠抗人单克隆抗体预防及治疗尸肾移植后排斥反应的效果。方法 总结和分析了６２例肾移植后应用鼠抗人单克隆抗体ＷｕＴ３、ＴｕＴ４预防及治疗排斥反应的效果、单克隆体治疗期间血清游离单克隆抗体水平与受者抗鼠抗体的产生等情况。结果 该抗体对急性排斥反应的总体治愈率为７６．１％,对耐激素的难治性排斥反应的逆转率达６０．７％;ＣＤ３和ＣＤ４的抑制效应与血清游离单克隆抗体浓度密切相关;首次应用单克隆抗体治     

静脉注射用免疫球蛋白对降低高致敏肾移植受者群体反应性抗体的作用

目的 观察并分析静脉注射用免疫球蛋白(IVIG)在高致敏受者肾移植中的应用效果.方法 回顾性分析18例群体反应性抗体(PRA)阳性的高致敏肾移植受者的临床资料,所有受者均应用IVIG进行治疗.观察治疗后受者的抗体水平、术后排斥反应发生率,并结合文献资料对IVIG的应用进行综合评价.结果 应用IVIG前,18例受者中有2例PRA水平为100%,4例＞70%、8例＞50%、4例＞30%,应用IVIG后所有受者PRA水平明显下降,其中2例受者转为全阴性,15例受者抗HLA-Ⅰ类和抗HLA-Ⅱ类抗体＜30%,两者比较,差异有统计学意义(P＜0.01),应用IVIG后肾移植效果良好,受者术后急性排斥反应发生率为38.5%,未出现移植肾的丢失.结论 应用IVIG能有效降低高致敏肾移植受者的PRA水平,联合应用生物抗体和免疫抑制剂可以使更多高致敏受者获得肾移植机会,并且术后应用IVIG具有抗排斥反应作用.     

Use of tacrolimus and mycophenolate mofetil as induction and maintenance in simultaneous pancreas‐kidney transplantation

Abstract Clinical trials using quadruple immunosuppression that include the combination of tacrolimus and mycophenolate mofetil have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas‐kidney (SPK) transplantation. In an attempt to obtain a low rejection rate without antibody induction therapy, we undertook a prospective study of combined tacrolimus and mycophenolate mofetil and steroids as primary immunosuppression for SPK transplantation. In this study, we analyzed 17 patients who received low‐dose intravenous tacrolimus as induction therapy. This was combined with oral tacrolimus, mycophenolate mofetil, and steroids as the primary immunosuppression regimen. There was a significant reduction of empirically and biopsy‐proven rejection with an incidence of 23 % (4 patients). Leukopenia, gastroparesis, and gastrointestinal side‐effects were the cause of discontinuation of mycophenolate mofetil, or low tacrolimus trough level in those patients who developed rejection. All rejection episodes were easy to treat, and none of them required antibody therapy. The combination of tacrolimus with mycophenolate mofetil without antibody induction therapy is effective in preventing early acute rejection. This combination is safe and effective as an alternative immunosuppressive regimen after SPK transplantation.     

Induction immunosuppression

Induction immunosuppression is intense, prophylactic therapy used at the time of transplantation based on the empiric observation that more powerful immunosuppression is required to prevent acute rejection early. In the past decade, there has been a growing trend towards the use of specialized agents such as antibody therapies for induction. In general, these agents have been shown to reduce the rate of acute rejection. However, their use has not been clearly shown to improve long-term transplant outcomes. This overview will review the biological basis for induction immunosuppression and the mechanisms of action of those specialized induction agents currently in clinical use. Clinical trials investigating induction regimens will be evaluated, and an individualized approach to the use of induction immunosuppressants will be presented.     

The role of alemtuzumab in facilitating maintenance immunosuppression minimization following solid organ transplantation

National registry data indicate a trend towards the incorporation of lymphocyte depletion antibody induction therapy into immunosuppressive regimens for solid organ transplantation. Depletional induction has been shown to reduce the risk of early acute rejection, but increase the risk of immune incompetence. As such, it recently has been paired with reduced maintenance immunosuppression in an effort to curb excessive immunosuppression without sacrificing low rejection rates. Alemtuzumab is a humanized CD52-specific monoclonal antibody that has been used in the setting of maintenance immunosuppression minimization. Although not specifically indicated for organ transplantation, it is now used off-label as an induction agent in approximately 10% of transplant recipients in the United States. In general, alemtuzumab is well tolerated and substantially reduces the risk of acute rejection in the first 6 months post-transplant in non-sensitized recipients. There is little evidence to support the notion that it uniquely promotes tolerance, and growing evidence that it is ineffective in the setting of allosensitization. Alemtuzumab-treated patients clearly remain dependent on maintenance immunosuppression. Long-term outcome data will be required to determine the magnitude and type of maintenance therapy that makes best use of alemtuzumab's depletional effects.     

Withdrawal of steroid therapy in African American kidney transplant recipients receiving sirolimus and tacrolimus

BACKGROUND: Withdrawal of corticosteroids from the immunosuppressive regimens of kidney transplant recipients has been associated with an increased risk of acute and chronic allograft rejection. Previous studies indicate that the risk of rejection is particularly high in African Americans. METHODS: We prospectively enrolled 44 African American kidney transplant recipients to participate in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids. No patient received antibody induction therapy. Prednisone was withdrawn from eligible patients free of acute rejection beginning as early as 3 months posttransplant, and followed for a minimum of 9 months posttransplant. Patients were followed for acute rejection and for changes in blood pressure, body weight, and serum creatinine concentrations before and after withdrawal of steroids. RESULTS: Thirty of 44 patients (68%) were weaned off of prednisone. Follow-up after withdrawal of prednisone ranged from 3 to 26 months (mean, 14.3+/-7.7 months). Two of 30 patients (6.7%) developed acute rejection. At last follow-up, 27 of 30 patients (90%) remain steroid-free. Steroid withdrawal was associated with significant reductions in blood pressure. CONCLUSIONS: Use of sirolimus and tacrolimus, without the use of induction antibody therapy, allows withdrawal of prednisone as early as 3 months posttransplant with low rates of subsequent acute rejection in African American kidney transplant recipients. Withdrawal of prednisone was associated with lower blood pressures and the need for fewer antihypertensive medications.     

抗体诱导治疗在肝移植中的应用进展

应用生物蛋白制剂——抗体作为器官移植早期实施免疫抑制覆盖治疗的方法,可显著减少器官移植术后早期急性排斥反应的发生,且未显著增加移植后感染发生率,同时可延迟或减少CNI的应用,有利于保护肾功能、促进移植物功能恢复及受者长期存活。本文通过总结常见抗体免疫诱导剂的特点及作用机制,分析不同抗体诱导治疗应用于肝移植的临床获益与风险,为肝移植抗体诱导剂的合理使用提供参考。     

Humanized anti-CD154 antibody therapy for the treatment of allograft rejection in nonhuman primates

The anti-CD154 antibody hu5C8 prevents acute allograft rejection and prolongs allograft survival after withdrawal of therapy in nonhuman primates. This study describes the use of hu5C8 as a rescue agent for rejection developing after the withdrawal of hu5C8. Twelve rhesus monkeys that had received renal allografts under hu5C8 induction and subsequently rejected were studied. Rescue with hu5C8 was analyzed based on the histological character of the rejection (acute versus chronic) and whether conventional therapy was received at the time of rescue or induction. The diagnosis of rejection and response to therapy was based on allograft function and histology. Four monkeys that had acute rejection associated with conventional immunosuppression and hu5C8 were not reversed by hu5C8 rescue. Four animals with isolated chronic rejection following prolonged rejection-free survival after the withdrawal of hu5C8 did not respond to hu5C8 rescue therapy. Hu5C8 rescue therapy effectively reversed acute rejection occurring in two monkeys after hu5C8 withdrawal. One of two animals with combined acute on chronic rejection responded to hu5C8 rescue therapy. Hu5C8 effectively reverses acute but not chronic allograft rejection and appears to have no synergistic effect with conventional rescue agents.     

A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection

BACKGROUND: The CD40-CD154 interaction is critically important in the cell-mediated immune responses. Blockade of this costimulatory pathway has been shown to prevent acute allograft rejection in murine, as well as nonhuman primate models. However, the role of the CD40-CD154 pathway in the development of chronic rejection and the effects of CD154 targeting on progression of chronic rejection have not been evaluated. METHODS: We examined the effect of AH.F5, a new hamster anti-rat CD154 monoclonal antibody, in a fully allogeneic acute(u) into Lewis [LEW] (RT11) and chronic [WF.1L (RT1l) into LEW (RT1l)] vascularized cardiac allograft rejection model. In the chronic model, the antibody was evaluated for prevention (starting day of transplant) and interruption of progression (starting day 30 or 60 after transplant) of chronic vasculopathy. Graft survival, morphology, and immunohistology were evaluated. RESULTS: In the acute rejection model, anti-CD154 therapy alone prevented acute allograft rejection and resulted in 50% long-term allograft survival (>200 days) and donor-specific tolerance. In recipients treated with anti-CD154 monoclonal antibody in combination with a short course of cyclosporine, 100% of allografts survived long-term and all recipients achieved donor-specific tolerance. In the chronic rejection model, allografts from animals treated with the anti-CD154 antibody had a statistically significant lower score of graft arteriosclerosis and fibrosis in both the prevention and 30-day interruption groups when compared with control allografts. In addition, immunohistochemistry showed a decrease in intragraft mononuclear cell infiltration and activation. CONCLUSION: A new anti-CD154 antibody not only prevents acute allograft rejection, but also inhibits and interrupts the development of chronic rejection. In the acute rejection model cyclosporine acts synergistically with anti-CD154 therapy to prolong allograft survival and induce tolerance. In the chronic rejection model relatively early initiation of therapy is essential to prevent progression of chronic allograft vasculopathy and fibrosis.     

Renal transplantation with early steroid withdrawal

Steroids are effective immunosuppressants in renal transplantation but are associated with significant adverse effects. As a result, there has been increased interest in protocols utilizing steroid minimization. Initial trials stopped steroids at approximately 3 months, when the highest risk phase for acute rejection was over. As two randomized trials using cyclosporine and mycophenolate mofetil without induction therapy showed an unacceptably high acute rejection rate, more recent interest has focused on the cessation of steroids very early, usually within the first week after transplantation. Most protocols have used antibody induction combined with calcineurin inhibitors and mycophenolic acid derivatives. Uncontrolled studies have shown a low rate of acute rejection, but the most recent randomized controlled trials have demonstrated an increased risk of acute rejection. These trials have not shown any consistent difference in short-term patient or graft survival. Cardiovascular risk factors do not appear to be consistently improved by early steroid withdrawal. Most trials lack sufficient follow-up (5 years or more) to assess the impact of the increased acute rejection rate seen with early steroid withdrawal on long-term outcomes. Thus, the use of such protocols remains investigational.     

Early experience with two-dose daclizumab in the prevention of acute rejection in cardiac transplantation

BACKGROUND: Daclizumab is a human monoclonal antibody that binds to the interleukin-2 receptor. It has been used as induction therapy in heart transplantation with repeated administrations over several weeks. At our institution, we use a two-dose regimen of daclizumab based on its extended half-life. We sought to determine the incidence of acute rejection with 2-dose daclizumab in cardiac transplantation. METHODS: Eighteen consecutive heart transplants performed at a single center were analyzed retrospectively. Patients received daclizumab (2 mg/kg) within 8 h of cardiac transplantation and a second dose (1 mg/kg) 2 wk thereafter. Maintenance immunosupression included mycophenolate mofetil, prednisone and either cyclosporine or tacrolimus, based on side-effect profile. The endpoint was the incidence of acute rejection as defined by a histologic grade >2 according to the classification of the International Society of Heart and Lung Transplantation. RESULTS: Four patients had acute rejections (all were 3A) during the first 3 months post-transplantation. All four patients had rejection at the first biopsy and only two had rejection thereafter. None of the rejections were hemodynamically significant and no patients were hospitalized. All except one rejection was seen in the context of low 2-h cyclosporine levels. The two-dose regimen was easier to administer on an outpatient basis and resulted in lower cost. CONCLUSIONS: This preliminary report suggests that induction therapy with a two-dose regimen of daclizumab appears to be safe and well tolerated in patients undergoing cardiac transplantation.     

The use of intravenous tacrolimus and mycophenolate mofetil as induction and maintenance immunosuppression in simultaneous pancreas--kidney recipients with previous transplants

Clinical trials using quadruple immunosuppression that include the combination of tacrolimus (TAC) and mycophenolate mofetil (MMF) have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas-kidney (SPK) transplantation. In attempting to obtain a low rejection rate without antibody induction therapy, we proceeded with the combination of TAC intravenous (i.v.), MMF, and steroids as induction therapy and as primary immunosuppression for recipients with previous transplants. In this study, we analyzed 10 patients who received previous transplants, treated with low-dose TAC i.v. as induction therapy. Group A consisted of 6 patients with previous transplants that underwent SPK and group B consisted of four recipients with previous SPK that underwent cadaveric kidney transplants. For group A, the previous transplants were: living related kidney (LRK) followed by islet cell (IC) transplant (n=2), LRK transplant (n=1), cadaver kidney (CAD) and IC transplant (n=1), SPK (n=1), and three previous CAD kidney transplants (n=1). In group A, all six kidneys were lost due to recurrent diabetic nephropathy, IC possibly to rejection, and the pancreas due to thrombosis. In group B with previous SPK transplants, three recipients lost their kidney to chronic rejection and one to long-term use of a nephrotoxic antibiotic. Currently, in all group A and B patients, the kidney and the pancreas are functioning, although 1 patient in group A developed type 2 diabetes (normal fasting C-peptide). Two patients in group A developed three rejection episodes that responded to steroid treatment. The results indicate the TAC i.v. in combination with oral TAC, MMF, and steroids offer effective induction therapy in patients with previous transplants.