Pharmacologic immunosuppression
Pharmacologic immunosuppression
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DOI：
10.2741/1249
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发表时间：
2004-01-01
影响因子：
3.1
通讯作者：
Goss, JA
中科院分区：
文献类型：
--
作者：
Barshes, NR;Goodpastor, SE;Goss, JA
临床器官移植只有在有效的药物免疫抑制出现后才成为一种可行的治疗选择。硫唑嘌呤和类固醇是首批可用于药理免疫抑制的药物，使肾和肝移植首次获得长期成功，尽管幸存者经历了免疫抑制的显著不良影响。硫唑嘌呤是一种抗代谢药物，可抑制嘌呤合成的从头合成和挽救途径。这会导致淋巴细胞抑制，但也会对骨髓、胃肠道和肝脏产生毒性。霉酚酸酯(MMF)是另一种抗代谢药物，它只抑制从头合成嘌呤的途径。皮质类固醇主要通过封闭网状内皮系统中的CD+T淋巴细胞和抑制细胞因子的转录而引起免疫抑制。皮质类固醇对人体内几乎每一个系统都有不良影响，会产生许多限制剂量的问题，如骨质疏松症、肥胖和糖耐量低减。1983年引入环孢菌素后，移植物存活率进一步提高，急性排斥反应的发生率降低。环孢素和最近推出的他克莫司组成了一类被称为钙调神经磷酸酶抑制剂的免疫抑制剂。通过结合钙调神经磷酸酶并阻止其移位到细胞核，这些药物阻止了IL-2的转录和随后的分泌。这些药物会产生不同程度的肾毒性、神经毒性和葡萄糖耐量异常。雷帕霉素也抑制IL-2的表达，虽然是通过与哺乳动物的雷帕霉素靶蛋白(MTOR)相互作用。利用抗体产生免疫抑制始于在马或山羊等动物身上开发的多克隆血清。多克隆血清导致免疫抑制的机制尚不清楚，尽管循环中淋巴细胞的细胞介导的细胞毒性可能是主要作用之一。相比之下，单抗OKT3是针对T细胞受体(TCR)/CD3复合体的，因此可以防止T淋巴管的激活。最近，人和嵌合鼠单抗Daclizumab和basiliximab提供了有效的诱导治疗，几乎没有不良反应。尽管免疫抑制剂的疗效提高和不良反应减少占了移植领域进展的很大一部分，但目前的免疫抑制药物并不完美。理想情况下，药物可诱导移植物耐受，同时避免全身免疫抑制和非免疫学不良反应。未来的研究可能会集中在分子和基因水平的机制上，以实现这一目标。
Clinical organ transplantation only became a viable treatment option after the advent of effective pharmacologic immunosuppression. Azathioprine and steroids were among the first drugs available for pharmacologic immunosuppression allowed for the first long-term successes in kidney and liver transplantation, though survivors experienced significant adverse effects of the immunosuppression. Azathioprine is an antimetabolite which inhibits the de novo and salvage pathways of purine synthesis. This results in lymphocyte suppression but also toxicity to bone marrow, gastrointestinal tract, and liver. Mycophenolate mofetil (MMF), another antimetabolite drug, inhibits only the de novo purine synthesis pathway. Corticosteroids cause immunosuppression mainly by sequestration of CD 4+ T-lymphocytes in the reticuloendothelial system and by inhibiting the transcription of cytokines. Corticosteroids have adverse effects on virtually every system in the body, producing many dose-limiting problems such as osteoporosis, obesity and glucose intolerance.The introduction of cyclosporine in 1983 allowed for further improvements in graft survival, and the incidence of acute rejection decreased. Cyclosporine and the more recently-introduced tacrolimus compose the class of immunosuppressive agents called calcineurin inhibitors. By binding calcineurin and preventing its translocation into the nucleus these drugs prevent transcription and subsequent secretion of IL-2. These drugs produce varying degrees of nephrotoxicity, neurotoxicity and glucose intolerance. Rapamycin also inhibits IL-2 expression, though by interaction with the mammalian Target of Rapamycin ( mTOR) protein.The use of antibody to produce immunosuppression began with polyclonal sera developed in animals such as horses or goats. The mechanism by which polyclonal sera causes immunosuppression is not well understood, though cell-mediated cytotoxicity of lymphocytes in the circulation may be one major effect. In contrast, the monoclonal antibody OKT3 is specific for the T-cell receptor (TCR) / CD3 complex, thus preventing activation of T-lymphocutes. Most recently, human and chimeric murine monoclonal antibodies daclizumab and basiliximab have provided effective induction therapy with virtually no adverse effects.While the improved efficacy and decreased adverse effects immunosuppressive agents account for much of the progress in the field of transplantation, current immunosuppression medications not perfect. Ideally, medications would inducing graft tolerance while avoiding generalized immunosuppression and non-immunologic adverse effects. Future research will likely focus on molecular- and gene-level mechanisms to achieve this goal.