Molecular mechanisms of new immunosuppressants.
Molecular mechanisms of new immunosuppressants.
复制标题
新型免疫抑制剂的分子机制。
作者：
P. Halloran
维持性免疫抑制药物通过部分阻断免疫反应中的限速步骤来发挥作用。新的维持性免疫抑制药物要么是核苷酸（嘌呤或嘧啶）从头合成的抑制剂，要么是抑制淋巴细胞信号转导的亲免素结合药物。新的核苷酸从头合成抑制剂包括吗替麦考酚酯 (MMF)、咪唑立宾 (MZ)、布喹那 (BQR) 和来氟米特 (LEF)。 MMF 和 MZ 通过抑制肌苷单磷酸脱氢酶 (IMPDH) 来抑制嘌呤从头合成。它们会导致 T 和 B 淋巴细胞选择性免疫缺陷。 MMF 水解为霉酚酸 (MPA)，它是 IMPDH 的非竞争性抑制剂。 MPA 会减少鸟嘌呤核苷酸库，并增加一些腺嘌呤核苷酸，从而抑制细胞周期。因此，通过限制克隆扩张，可以减少特异性效应T淋巴细胞和B淋巴细胞的数量。 MZ 是 IMPDH 的竞争性抑制剂，会产生类似的缺陷。 MMF 与 MZ 的相对临床疗效尚不清楚。 MMF已在多个国家获得批准； MZ已在日本获得批准。嘧啶从头合成抑制剂（BQR、LEF）作用于脱氢乳清酸脱氢酶。目前两者均未进行移植临床试验。新型亲免素结合药物可抑制钙依赖性磷酸酶钙调神经磷酸酶 (CN) [他克莫司（或 FK-506）和环孢菌素 (CsA) 微乳形式] 或生长因子受体 [雷帕霉素（西罗莫司）] 的信号传导。他克莫司与 FK 结合蛋白 12 (FKBP-12) 结合，形成抑制 CN 的复合物。 CsA 与亲环蛋白结合形成抑制 CN 的复合物。 CN 的抑制可防止 T 细胞中细胞因子基因的激活。他克莫司与微乳 CsA 的相对临床疗效尚不清楚。雷帕霉素抑制生长因子受体（例如 IL-2R）的信号传导。雷帕霉素与 FKBP 结合形成一种复合物，该复合物与称为 TOR（雷帕霉素靶标）或 RAFT（雷帕霉素和 FKBP 靶标）的蛋白质（可能是激酶）结合。结果是细胞因子受体激活细胞周期的能力受到阻碍，干扰克隆表达。 Deoxyspergualin 是一种正在开发的用于诱导或抗排斥治疗的肠胃外药物，可能会抑制热休克蛋白家族成员 Hsc70 的细胞内伴侣作用。它的主要作用可能是通过抑制抗原呈递细胞和单核细胞中转录因子 NF-κ B 的激活。
Maintenance immunosuppressive drugs act by partially blocking rate-limiting steps in the immune response. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The new inhibitors of de novo nucleotide synthesis include mycophenolate mofetil (MMF), mizoribine (MZ), brequinar (BQR), and leflunomide (LEF). MMF and MZ act to inhibit de novo purine synthesis, by inhibition of inosine monophosphate dehydrogenase (IMPDH). They create a selective immunodeficiency in T and B lymphocytes. MMF is hydrolyzed to mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH. MPA reduces the pools of guanine nucleotides, and increases some adenine nucleotides, inhibiting the cell cycle. Thus the number of specific effector T and B lymphocytes is reduced by limiting clonal expansion. MZ is a competitive inhibitor of IMPDH, which creates a similar defect. The relative clinical effectiveness of MMF versus MZ is not known. MMF has been approved in a number of countries; MZ has been approved in Japan. The inhibitors of de novo pyrimidine synthesis (BQR, LEF) act on the enzyme dehydroorotate dehydrogenase. Neither is currently in clinical trials in transplantation. The new immunophilin-binding drugs inhibit either the calcium-dependent phosphatase calcineurin (CN) [tacrolimus (or FK-506) and the microemulsion form of cyclosporine (CsA)] or signaling from growth factor receptors [rapamycin (sirolimus)]. Tacrolimus binds to FK binding protein-12 (FKBP-12) to create a complex that inhibits CN. CsA binds to cyclophilin to create a complex that inhibits CN. Inhibition of CN prevents activation of cytokine genes in T cells. The relative clinic effectiveness of tacrolimus versus microemulsion CsA is unknown. Rapamycin inhibits signaling from growth factor receptors, such as IL-2R. Rapamycin binds to FKBP to create a complex that engages proteins called TOR (target of rapamycin), or RAFT (rapamycin and FKBP target), which may be kinases. The result is a block in the ability of cytokine receptors to activate cell cycling, interfering with clonal expression. Deoxyspergualin, a parenteral drug in development for induction or antirejection therapy, may inhibit intracellular chaperoning by Hsc70, a member of the heat shock protein family. It may have its principal effect by inhibiting the activation of transcription factor NF-kappa B in antigen-presenting cells and monocytes.