达利珠单抗预防致敏受者肾移植后排斥反应的临床研究

目的　探讨用达利珠单抗诱导治疗预防致敏受者肾移植后急性排斥反应的有效性与安全性。方法　将 36例群体反应性抗体为 30 %～ 5 0 %的致敏受者随机分为舒莱组和对照组 ,各 18例 ,舒莱组患者于移植术前 2h和术后第 4d接受达利珠单抗 (2 0mg/次 )诱导治疗 ,两个组术后均以环孢素A、霉酚酸酯和皮质激素预防排斥反应。结果　舒莱组术后 3个月内的急性排斥反应发生率明显低于对照组 (P <0 .0 1) ;术后 2～ 4周内对照组平均每日皮质激素用量明显高于舒莱组 ;两个组人 /肾 1年存活率的差异无显著性 ;舒莱组术后肾功能的恢复较对照组快 ,但差异无显著性 ;舒莱组术后1周内CD2 5 淋巴细胞数明显降低 (P <0 .0 1) ;未观察到达利珠单抗的相关不良反应。结论　在合理筛选供受者的基础上 ,致敏受者肾移植前接受达利珠单抗诱导治疗可降低术后急性排斥反应的发生率 ,且较为安全。     

Following Anti-CD25 Treatment, A Functional CD4+CD25+ Regulatory T-Cell Pool Is Present in Renal Transplant Recipients

Daclizumab, a humanized antibody directed against the alpha-chain of the interleukin-2 receptor (CD25), has shown efficacy in the prevention of acute rejection following organ transplantation. However, anti-CD25 therapy can be expected to affect not only alloreactive effector T cells, but also CD4(+)CD25(+) regulatory T (Treg) cells that are shown to play an important role in the induction of transplantation tolerance. Therefore, the size and function of the Treg pool in human renal allograft recipients after single-dose daclizumab administration was investigated in this study. Approximately 8 weeks after administration, daclizumab was cleared from the circulation and the Treg population then present appeared not different from that observed before transplantation. Functional analysis revealed that the Treg possessed a normal capacity to suppress mixed lymphocyte reactions in vitro. These data indicate that after daclizumab therapy a Treg population, normal in number and function, is present in the peripheral blood of renal transplant recipients.     

赛尼哌在肝移植中的应用探讨

目的研究赛尼哌在肝移植患者中应用的安全性和有效性 ,探讨其在肝移植中的合理应用方案。方法对 2 0 0 1年 3月到 2 0 0 3年 2月间 5 0例有肾功能不全或有肾功能不全高危因素的肝移植患者应用赛尼哌情况进行回顾性研究。结果与对照组相比以下时期血肌酐水平显著增高 :移植前 (12 6± 5 5 )mmol/L ,P =0 0 0 2 7;术后第 1天 (16 4± 6 0 )mmol/L ,P =0 0 0 14 ;术后第 7天(12 0± 2 8)mmol/L ,P =0 0 179。术后第 14天 (99± 2 6 )mmol/L与对照组比差异无显著意义 ,P =0 4 0 0 7。应用赛尼哌期间未见有其他重要脏器功能损害。急性排斥反应的发生率 :治疗组 6 % (3/5 0 ) ,对照组 2 9% (18/ 6 2 ) ,P =0 0 0 19。感染的发生率 :治疗组 5 6 % (2 8/ 5 0 )。对照组 5 8% (36 / 6 2 ) ;P =0 82 6。结论赛尼哌在肝移植中应用安全有效 ,有利于肾功能不全的恢复 ,不增加感染的发生率 ,不引起重要脏器功能不全。联合应用赛尼哌 ,可减低钙调神经磷酸酶抑制剂 (calcineurininhibitor,CNI)的血药浓度 ,在术后早期推迟CNI的应用时间 ,同时明显减低急性排斥反应的发生率。     

Effect of Anti-IL-2Rα Antibody on IL-2-induced Jak/STAT Signaling

Acute allograft rejection is driven by production of cytokines such as interleukin-2 (IL-2) that activate and expand alloreactive T cells by ligating high-affinity IL-2 receptors composed of three subunit chains: alpha, beta, gamma The alpha chain, expressed only on activated T cells, has become an important therapeutic target. Monoclonal antibodies (mAbs) that bind IL-2Ralpha chains significantly decrease transplant rejection. We examined the ability of the humanized anti-IL-2Ralpha antibody daclizumab to block high-affinity IL-2Rs and interrupt T-lymphocyte signaling. Our evaluation focused on a pathway critical for T-cell proliferation, the Jak/STAT pathway. Daclizumab markedly inhibited phosphorylation of the Jak1, Jak3 and STAT5a/b components of the IL-2R-dependent pathway. Suppression by daclizumab was associated with internalization of IL-2Ralpha but not IL-2Rbetagamma chains. High IL-2 doses overcame daclizumab-induced blockade of Jak/STAT phosphorylation despite absent cell surface highaffinity IL-2Rs. Under these circumstances, IL-2-mediated Jak/STAT pathway activation might be generated through residual intermediate affinity IL-2Rbetagamma receptors, and this was demonstrated by complete blockade of signaling when anti-IL-2Rbeta monoclonal antibody was added. Humanized antibodies are an important part of strategies to induce alloantigen tolerance. Understanding the molecular events associated with their beneficial clinical effect is critical to design of future immunosuppressive strategies.     

Is it worth using daclizumab induction therapy with mycophenolate mofetil-based immunosuppressive regimens in live related donor kidney transplantation? A long-term follow up

Background/Aims The aim of this work is to determine the long-term therapeutic benefit(s) of daclizumab induction therapy with triple immunosuppressive protocols including prednisolone, cyclosporine microemulsion (CsA), and mycophenolate mofetil (MMF) in the living related donor kidney transplantation. Methods Twenty-one adult recipients of their first kidney allograft were allocated to receive daclizumab with triple immunosuppressive therapy (steroids, CsA, and MMF). They were compared to 50 recipients of their first grafts who received a maintenance triple immunosuppressive therapy (steroids, CsA, and azathioprine). The patients were followed up for 5 years. Results Daclizumab group significantly experienced a marked reduction of acute rejection (7/21) when compared to the control group (31/50) with subsequent significant reduction of cumulative steroids doses at the end of 5 years. The overall incidence of post-transplant complications was comparable among the two treatment groups. There was no significant difference in patients and graft survival; 5-year patient and graft survival were 95.3%, 85.7% for daclizumab and 96%, 88% for control group, respectively. Conclusions Although prophylactic daclizumab with triple immunosuppressive protocol including MMF have drastically reduced the incidence of acute rejections, the graft and patient survival are unchanged in this long-term follow up.     

Repeated daclizumab administration to delay the introduction of calcineurin inhibitors in heart transplant patients with postoperative renal dysfunction

Daclizumab is an interleukin-2 receptor antagonist which is used for induction therapy in heart transplant patients. It has few side effects and is associated with a low infection rate. Postoperative renal failure after heart transplantation is common and potentially fatal. The administration of calcineurin inhibitors in the postoperative period can aggravate the situation. We report the cases of six patients who underwent heart transplantation and developed acute renal failure in the immediate postoperative period. All were administered daclizumab weekly to avoid the introduction of calcineurin inhibitors and to facilitate recovery of renal function. Calcineurin inhibitors were introduced only once renal function had improved. Renal function recovered in all cases and there was a low complication rate. The administration of repeated doses of daclizumab to patients who experience acute postoperative renal failure after heart transplantation may provide an alternative therapeutic approach that enables calcineurin inhibitors to be avoided and, consequently, renal function to recover.Full English text available from:www.revespcardiol.org     

Daclizumab for the treatment of adults with relapsing forms of multiple sclerosis

Introduction: The goal of the article is to review the mechanism of action and the use of daclizumab, a humanized monoclonal antibody (mAb) against the alpha subunit of the high affinity interleukin-2 (IL-2) receptor, in the treatment of Multiple Sclerosis (MS).

Areas covered: PubMed was searched for the terms ‘daclizumab’ and ‘multiple sclerosis’. The mechanisms of action, pharmacokinetics and pharmacodynamics, major studies, side effects and drug interactions of daclizumab in MS are discussed.

Expert commentary: Monthly daclizumab-beta [DAC-beta, formerly daclizumab high yield process (DAC HYP), approved as ZINBRYTA®, which has a different form and structure than an earlier form of daclizumab], is an effective and convenient treatment option for patients with relapsing forms of MS who have failed other treatment, or as a first-line option in highly active MS patients. IL-2 signaling modulation by daclizumab constitutes a novel mechanism of action which may also underlie the adverse and serious adverse events and risk profile of the drug that requires appropriate patient selection, monitoring and risk-mitigation programs.     

Daclizumab and Alemtuzumab as induction agents in adult intestinal and multivisceral transplantation: A comparison of two different regimens on 29 recipients during the early post-operative period

INTRODUCTION: Induction therapy has been recently adopted for intestinal transplant. PATIENTS AND METHODS: We compared during first 30 days post-transplantation 29 recipients, allocated in two groups, treated with Daclizumab (Zenapax) or Alemtuzumab (Campath-1H). RESULTS: During first month, 45% of Daclizumab recipients experienced six acute cellular rejections (ACRs) of mild degree, while 63% of them developed an infection requiring treatment. We found three acute cellular rejections in 17.6% of Alemtuzumab recipients, two with moderate degree; 64.7% of them required treatment for infection. DISCUSSION AND CONCLUSIONS: Graft and patient 3-years cumulative survival rate were not significantly different between groups. Alemtuzumab seems to offer a better immunosuppression during first month.     

肾移植中2剂舒莱和2剂赛尼哌对外周血可溶性白细胞介素-2受体水平的影响及意义

目的:探讨2剂舒莱和2剂赛尼哌在尸体肾移植中对外周血可溶性白细胞介素2受体(sIL2R)水平的影响及意义。方法:105例首次接受尸体肾移植的受者随机分为舒莱组、赛尼哌组和对照组,所有受者术后均接受普乐可复或环孢素A加骁悉加泼尼松三联疗法。另外舒莱组在术前2h、术后4天静脉滴注20mg舒莱,赛尼哌组在前24h、术后7天静脉滴注50mg赛尼哌。检测各组术前及术后每周共8周外周血中sIL2R水平变化,记录2个月内急性排斥(AR)的例数。结果:舒莱和赛尼哌组外周血中sIL2R水平分别在术后8周和3周内比对照组低(P<0.05)。术后第4～6周舒莱组比赛尼哌组低(P<0.05)。在术后2个月内,舒莱组、赛尼哌组和对照组发生急性排斥反应的例次分别为1、9、17例,各组比较差异有统计学意义(P<0.05)。结论:2剂舒莱对外周血中sIL2R的抑制及抗急性排斥反应效果比2剂赛尼哌好。     

Promising emerging therapies for multiple sclerosis

Until recently, interferon beta and glatiramer acetate were the only licensed disease-modifying therapies for relapsing forms of multiple sclerosis. These agents have a modest effect on reducing relapse rates. The licensing of two more effective agents, mitoxantrone and natalizumab, provided alternatives. These agents are associated with potentially life-threatening or serious side effects. In addition, none of these licensed agents has been shown to be effective in primary progressive MS. There is a large unmet need, with several promising new therapies in the pipeline. This article reviews the proposed mechanisms of action of the anticipated treatments, their efficacy, and risks associated with their use.