Clinical update: immunosuppression minimisation
Clinical update: immunosuppression minimisation
复制标题
DOI：
10.1016/s0140-6736(07)60762-4
复制
发表时间：
2007-05-20
期刊：
影响因子：
168.9
通讯作者：
Remuzzi, Giuseppe
中科院分区：
文献类型：
--
作者：
Sayegh, Mohamed H.;Remuzzi, Giuseppe
几十年来，移植中免疫抑制的主要原理一直是基于使用联合治疗。该策略的目的是针对不同的免疫反应机制来控制器官排斥反应并维持移植物的长期功能，最大限度地减少整体免疫抑制以避免感染和恶性肿瘤，并防止药物特异性毒性作用。上世纪80年代初，钙调磷酸酶抑制剂环孢素（ciclosporin）被引入肾移植临床应用，取得了两大成就：第一，显著降低急性排斥反应率，提高移植体短期存活率；第二，扩大实体器官移植程序，包括肝脏、胰腺、心脏和肺。直到1995年，移植专家在设计合理的联合免疫抑制策略方面能力有限，大多数患者维持环孢素、硫唑嘌呤和类固醇的三联治疗。环孢素是唯一一种被批准改善移植物生存的免疫抑制剂，但这种益处仅限于短期的1年生存数据。环孢素的主要毒性作用之一是肾功能障碍，包括肾小球滤过率的急性功能下降、血管病变的慢性结构改变和进行性纤维化，这本身可能导致慢性同种异体移植肾病的发展，这是同种异体移植肾长期慢性消耗的主要原因。1免疫抑制药物的研究和这些研究的终点通常集中在移植后6个月至1年的急性排斥率，很少关注后期终点，如移植物功能，移植物或患者的生存，以及移植物功能障碍的新终点和生物标志物。1995年至1999年间，几种新的免疫抑制药物被引入器官移植临床应用（表）。这些药物包括新配方的环孢素、他克莫司（另一种钙调磷酸酶抑制剂）、霉酚酸酯（嘌呤合成抑制剂）、西罗莫司（雷帕霉素[TOR]抑制剂的靶点）和白细胞介素-2受体抗体。这些药物和抗体被批准是因为它们减少了急性器官排斥反应，而不是因为它们提高了移植物的存活率。
For decades, the main principle of immunosuppression in transplantation has been based on the use of combination treatment. The aim of this strategy is to target distinct mechanisms of the immune response to control organ rejection and maintain long-term graft function, to minimise overall immunosuppression to avoid infections and malignancy, and to prevent drug-specific toxic effects. The introduction of the calcineurin inhibitor, ciclosporin, for clinical use in kidney transplantation in the early 1980s, resulted in two major achievements: first, substantial lowering of acute rejection rates and improvement in short-term graft survival; and second, expansion of solid-organ transplantation procedures to include the liver, pancreas, heart, and lung.Until 1995, transplant specialists were limited in their abilities to devise rational combination immunosuppression strategies, and most patients were maintained on triple treatment with ciclosporin, azathioprine, and steroids. Ciclosporin was the only immunosuppressant ever approved that improved graft survival, but this benefit was limited to short-term 1-year survival data. One of the main toxic effects of ciclosporin is renal dysfunction, including an acute functional drop in glomerular filtration rate, chronic structural changes of vasculopathy, and progressive fibrosis, which itself might contribute to the development of chronic allograft nephropathy—the main cause of chronic attrition of renal allografts over time. 1 The study of immunosuppressive drugs and the endpoints of such studies have generally focused on acute rejection rates 6 months to 1 year after transplantation, and little attention has been paid to late endpoints, such as graft function, survival of the graft or patient, and novel endpoints and biomarkers of graft dysfunction. Between 1995 and 1999, several new immunosuppressive drugs were introduced for clinical use in organ transplantation (table). These drugs included new formulations of ciclosporin, tacrolimus (another calcineurin inhibitor), mycophenolate mofetil (purine synthesis inhibitor), sirolimus (a target of rapamycin [TOR] inhibitor), and antibodies to the interleukin-2 receptor. 2 These drugs and antibodies were approved because they decreased acute organ rejection, and not because they improved graft survival.