The case for local immunosuppression.
The case for local immunosuppression.
复制标题
局部免疫抑制的情况。
DOI：
10.1097/00007890-199207000-00001
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发表时间：
1992
期刊：
影响因子：
6.2
通讯作者：
S. Gruber
中科院分区：
文献类型：
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作者：
S. Gruber
器官移植在终末期肾脏、肝脏和心肺疾病的治疗中发挥了重要作用，移植物和患者存活率不断提高。然而，全身施用的免疫抑制剂目前以肾、肝、骨髓和其它器官功能障碍为代价来防止移植排斥。它们在目前接受的剂量方案中的使用促进了同种异体移植物接受者中感染、糖尿病和高血压的发展，并且与恶性肿瘤的风险增加相关。有三种主要的方法可以减少同种异体移植受体中全身免疫抑制的药物特异性和一般性不良后果，从而改善移植后的生活质量和持续时间：（1）治疗供体器官和/或移植患者以获得耐受性，其中宿主免疫系统对移植物特异性无反应，但在其他方面完全完整，因此不需要进一步的抗排斥治疗;（2）开发新的、无毒的免疫抑制剂，其特异性越来越强，从而最终只有识别移植物抗原的淋巴细胞的活性将被抑制，而宿主免疫系统的其余部分将不受影响;和（3）利用局部药物给药系统，通过药物递送的空间和时间控制，在移植器官中建立目前可用的非特异性免疫抑制剂的更有选择性的存在，同时减少全身药物暴露。虽然耐受性可以在各种动物模型中产生，并且耐受性机制的研究继续以快速的步伐进行（1，2），但具有可接受的风险/受益比的可行方案仍然难以广泛临床应用（3）。在过去十年中，泛T细胞单克隆抗体（OKT 3）的引入为移植免疫抑制增加了新的维度，但全身使用这种药物与感染（4-7）和淋巴瘤（8，9）的发病率和严重程度增加有关。最后，利用更特异性的抗CD 4（10）、抗IL-2受体（11，12）和抗细胞间粘附分子1（ICAM-1）*（13）单克隆抗体的实验和临床研究才刚刚开始。
Organ transplantation has assumed a major role in the treatment of end-stage renal, hepatic, and cardiopulmonary disease, with continued improvements in graft and patient survival. However, systemically administered immunosuppressive agents currently prevent transplant rejection at the cost of renal, hepatic, bone marrow, and other organ dysfunction. Their use in currently accepted dosage schedules promotes the development of infection, diabetes, and hypertension in allograft recipients, and is associated with an increased risk of malignancy. Three major approaches exist toward reducing the drugspecific and general adverse consequences of systemic immunosuppression in allograft recipients, and thereby improving the quality and duration of life following transplantation:(1) treatment of the donor organ and/or transplant patient to achieve tolerance, in which the host immune system is specifically unresponsive to the graft but otherwise completely intact, so that further antirejection therapy is unnecessary;(2) development of new, nontoxic immunosuppressants with increasingly greater specificity, so that eventually only the activity of lymphocytes that recognize graft antigens will be inhibited and the rest of the host immune system will be spared; and (3) utilization of local drug administration systems to establish a more selective presence of currently available nonspecific immunosuppressive agents in the transplanted organ through the spatial and temporal control of drug delivery, with a concomitant reduction in systemic drug exposure. Although tolerance can be produced in a variety of animal models and the investigation of tolerance mechanisms continues at a brisk pace (1, 2), feasible protocols with acceptable risk/benefit ratios for widespread clinical application remain elusive (3). The introduction of pan-T cell monoclonal antibody (OKT3) within the last decade has added a new dimension to transplant immunosuppression, but systemic use of this agent has been associated with an increased incidence and severity of infections (4–7) and lymphomas (8, 9). Finally, experimental and clinical studies utilizing the more specific anti-CD4 (10), anti-IL-2 receptor (11, 12), and antiintercellular adhesion molecule 1 (ICAM-1)*(13) monoclonal antibodies are just begin-