Barshes Neal R, Goodpastor Sarah E, Goss John A
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6550 Fannin. Suite 1628, Houston, TX 77030, USA.
Front Biosci. 2004 Jan 1;9:411-20. doi: 10.2741/1249.
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 CD4+ 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.
临床器官移植在有效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最早可用于药物免疫抑制的药物，它们使肾移植和肝移植首次取得长期成功，尽管幸存者经历了免疫抑制的显著不良反应。硫唑嘌呤是一种抗代谢物，它抑制嘌呤合成的从头合成途径和补救途径。这导致淋巴细胞受到抑制，但也对骨髓、胃肠道和肝脏产生毒性。霉酚酸酯（MMF），另一种抗代谢物药物，仅抑制嘌呤的从头合成途径。皮质类固醇主要通过将CD4 + T淋巴细胞隔离在网状内皮系统中以及抑制细胞因子的转录来引起免疫抑制。皮质类固醇对身体的几乎每个系统都有不良影响，产生许多剂量限制问题，如骨质疏松、肥胖和葡萄糖不耐受。1983年环孢素的引入使移植物存活率进一步提高，急性排斥反应的发生率降低。环孢素和最近引入的他克莫司构成了一类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转运到细胞核中，这些药物可防止白细胞介素-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、神经毒性和葡萄糖不耐受。雷帕霉素也抑制白细胞介素-2的表达，尽管它是通过与哺乳动物雷帕霉素靶蛋白（mTOR）相互作用来实现的。使用抗体产生免疫抑制始于在马或山羊等动物中产生的多克隆血清。多克隆血清引起免疫抑制的机制尚不完全清楚，尽管循环中淋巴细胞的细胞介导细胞毒性可能是一个主要作用。相比之下，单克隆抗体OKT3对T细胞受体（TCR）/CD3复合物具有特异性，从而阻止T淋巴细胞的激活。最近，人源和嵌合鼠源单克隆抗体达利珠单抗和巴利昔单抗提供了有效的诱导治疗，几乎没有不良反应。虽然免疫抑制剂疗效的提高和不良反应的减少是移植领域取得很大进展的重要原因，但目前的免疫抑制药物并不完美。理想情况下，药物应诱导移植物耐受，同时避免全身性免疫抑制和非免疫性不良反应。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。
