Land W G
Liaison Office Germany, Baskent University, Ankara, Turkey.
Transplant Proc. 2007 Apr;39(3):667-72. doi: 10.1016/j.transproceed.2007.01.052.
Experimental and clinical evidence has accumulated in support of the notion that oxidative injuries to allografts induce an adaptive alloimmune response which leads to acute rejection. The link between the initial injury and subsequent rejection is the innate immune system represented by injury-activated donor-derived and recipient-derived dendritic cells which interact with naïve T cells of the recipient to induce an alloimmune T-cell response. Therefore, time is mature to consider potential therapeutic strategies that are able to suppress events of innate immunity. Such strategies refer to a "time-restricted therapeutic window" that includes treatment of the donor during organ removal and the recipient during allograft reperfusion. Major targets of such treatment include (1) mitigation of the oxidative allograft injury; (2) inhibition of injury-induced activation of complement; (3) inhibition of Toll-like receptor (TLR)-mediated and innate lymphocyte-triggered maturation of dendritic cells; and (4) blockade of innate effector functions. A considerable variety of promising experimental studies about the prevention/inhibition of innate immune events has already been performed, including the successful experimental use of gene silencing methods, eg, using RNA interference technology with the application of small interfering RNA (siRNA). In addition, a few clinical trials with antioxidants (edaravone, SOD-mimetics), complement inhibitors (pexelizumab, TP-10) in patients with acute myocardial infarction, and TLR4 antagonists (TAK-242, E-5564) in patients with sepsis have been performed or are underway. Performance of similar clinical trials in transplant patients with antioxidative drugs, complement inhibitors, and/or TLR4 antagonists is urgently warranted; siRNAs appear to be extremely attractive for investigation in experimental allogeneic transplant models.
实验和临床证据不断积累，支持了这样一种观点：同种异体移植物的氧化损伤会引发适应性同种免疫反应，进而导致急性排斥反应。初始损伤与后续排斥反应之间的联系是由损伤激活的供体来源和受体来源的树突状细胞所代表的先天免疫系统，这些细胞与受体的初始T细胞相互作用，诱导同种免疫T细胞反应。因此，现在是时候考虑能够抑制先天免疫事件的潜在治疗策略了。此类策略涉及一个“时间限制治疗窗口”，包括在器官切除时对供体进行治疗，以及在同种异体移植物再灌注时对受体进行治疗。这种治疗的主要靶点包括：（1）减轻同种异体移植物的氧化损伤；（2）抑制损伤诱导的补体激活；（3）抑制Toll样受体（TLR）介导的以及先天淋巴细胞触发的树突状细胞成熟；（4）阻断先天效应功能。已经开展了大量关于预防/抑制先天免疫事件的有前景实验研究，包括成功地实验使用基因沉默方法，例如应用小干扰RNA（siRNA）的RNA干扰技术。此外，已经进行或正在进行一些针对急性心肌梗死患者使用抗氧化剂（依达拉奉、超氧化物歧化酶模拟物）、补体抑制剂（培昔单抗、TP - 10），以及针对脓毒症患者使用TLR4拮抗剂（TAK - 242、E - 5564）的临床试验。迫切需要在移植患者中开展使用抗氧化药物、补体抑制剂和/或TLR4拮抗剂的类似临床试验；siRNA在同种异体移植实验模型中的研究似乎极具吸引力。
