Vagefi Parsia A, Ierino Francesco L, Gianello Pierre R, Shimizu Akira, Kamano Chisako, Sachs David H, Yamada Kazuhiko
Transplantation Biology Research Center, Massachusetts General Hospital-Harvard Medical School, Boston, MA 02129, USA.
Transplantation. 2004 Apr 15;77(7):979-85. doi: 10.1097/01.tp.0000116416.10799.c6.
The authors' laboratory previously demonstrated that long-term tolerance to class I-disparate renal allografts in miniature swine can be induced by a short course of cyclosporine A (CsA), and that this stable tolerance is dependent on the presence of an intact thymus. In the present study, the authors have examined the requirement for a thymus during the pretransplant, induction, and maintenance phases of tolerance.
Twenty-two miniature swine underwent class I major histocompatibility complex-mismatched renal transplantation, with a 12-day course of CsA. Thymectomies were performed on days -21, 0, +8, +21, and greater than or equal to +42, in relation to the day of transplantation. Historical controls consisted of euthymic and sham-thymectomized recipients.
Euthymic, sham-thymectomized, and day-greater than or equal to +42 thymectomized recipients demonstrated stable renal function and minimal anti-donor cytotoxic T-lymphocyte (CTL) responses. In contrast, day -21 and day 0 thymectomized recipients demonstrated allograft dysfunction, marked cellular infiltrates, with severe vasculitis and glomerular changes, and strong anti-donor CTL responses. Animals thymectomized on days +8 and +21 did not undergo severe rejection, but likewise did not demonstrate a stable clinical course.
These data indicate that the requirement for thymic function in the induction of rapid and stable tolerance is greatest during the first 8 days and then diminishes over the next 2 weeks posttransplant. Failure of thymectomy to affect the course of tolerance after day +21 suggests that thymic function is not required for the maintenance of tolerance. Understanding the role of the thymus in establishing tolerance may permit the development of tolerance induction strategies, especially for pediatric transplant recipients.
作者所在实验室先前证明，通过短期使用环孢素A（CsA）可诱导小型猪对I类不相合肾移植产生长期耐受，且这种稳定耐受依赖于完整胸腺的存在。在本研究中，作者考察了在移植前、诱导和维持耐受阶段对胸腺的需求。
22只小型猪接受了I类主要组织相容性复合体不相配的肾移植，并接受了为期12天的CsA治疗。相对于移植日，在第-21天、0天、+8天、+21天以及大于或等于+42天进行胸腺切除术。历史对照包括有胸腺和假胸腺切除的受体。
有胸腺、假胸腺切除以及大于或等于+42天胸腺切除的受体表现出稳定的肾功能和最小的抗供体细胞毒性T淋巴细胞（CTL）反应。相比之下，第-21天和第0天胸腺切除的受体表现出移植物功能障碍、明显的细胞浸润、严重的血管炎和肾小球改变，以及强烈的抗供体CTL反应。在第+8天和第+21天进行胸腺切除的动物未发生严重排斥反应，但同样未表现出稳定的临床病程。
这些数据表明，在诱导快速稳定耐受过程中，胸腺功能的需求在移植后的前8天最大，然后在接下来的2周内逐渐减少。在+21天后胸腺切除未能影响耐受进程，这表明维持耐受不需要胸腺功能。了解胸腺在建立耐受中的作用可能有助于开发耐受诱导策略，特别是对于儿科移植受者。
