Koshiba Takaaki, Kitade Hiroaki, Van Damme Boudewijn, Giulietti Annapaula, Overbergh Lut, Mathieu Chantal, Waer Mark, Pirenne Jacques
Abdominal Transplant Surgery Department, Catholic University Leuven (KUL), Belgium.
Transplantation. 2003 Aug 15;76(3):588-96. doi: 10.1097/01.TP.0000080980.26287.11.
Regulatory cells prevent graft loss to acute rejection and induce tolerance, possibly by promoting Th2 deviation. Th2 cytokines stimulate B cells, which cause alloantibody-mediated chronic rejection. We searched to determine whether regulatory cell-mediated tolerance protects or not against chronic rejection.
Heart transplantation (Htx) was performed using RA (RT1P) and PVG (RT1c) rats as donor and recipients. Donor-specific blood transfusion (DSBT) was given on preTx day 12. Secondary grafts were implanted at day 100. Splenocytes were transferred from tolerant rats (and controls) into lightly irradiated (450 rad) naive PVG, which received RA Htx. Primary Htx were investigated for the development of vascular occlusion (VO), the production of Th1/Th2 intragraft cytokines, and for the nature of graft infiltrate as well as for endothelial deposition of immunoglobulin (Ig)G isotypes and complement (C3) binding. Results were compared with rejecting controls (no DSBT) and syngeneic Htx.
RA Htx were rejected within 10 days (8, 9, 10x4). PreTx DSBT prolonged primary Htx survival indefinitely (>140 days) with acceptance of secondary donor-specific (but not third-party) grafts (P<0.001). Naive irradiated PVG rats given splenocytes from tolerant rats but not from controls accepted RA Htx, showing the existence of regulatory cells in allograft acceptors. Despite being tolerant, DSBT-treated rats displayed typical features of chronic rejection at day 90 (VO=77%; P<0.001 vs. VO=4% in syngeneic rats). An overt Th2 deviation, particularly intragraft production of interleukin (IL)-4, was observed at day 30. Simultaneously to this Th2 deviation, B cells emerged in the grafts and endothelial deposition of IgG1 (Th2 dependent) and C3 binding were observed.
Regulatory cells that prevent graft loss to acute rejection in primary and secondary grafts do not protect against the development of chronic rejection.
调节性细胞可防止移植物因急性排斥反应而丧失，并诱导免疫耐受，可能是通过促进Th2偏移来实现的。Th2细胞因子刺激B细胞，而B细胞会引发同种异体抗体介导的慢性排斥反应。我们旨在确定调节性细胞介导的免疫耐受是否能预防慢性排斥反应。
以RA（RT1P）大鼠为供体、PVG（RT1c）大鼠为受体进行心脏移植（Htx）。在移植前第12天进行供体特异性输血（DSBT）。在第100天植入二次移植物。将来自耐受大鼠（及对照）的脾细胞转移至轻度照射（450拉德）的未致敏PVG大鼠体内，这些大鼠接受RA心脏移植。对初次心脏移植进行血管闭塞（VO）情况、移植物内Th1/Th2细胞因子产生情况、移植物浸润性质以及免疫球蛋白（Ig）G同种型的内皮沉积和补体（C3）结合情况的研究。将结果与排斥对照组（未进行DSBT）和同基因心脏移植进行比较。
RA心脏移植在10天内被排斥（8、9、10×4）。移植前DSBT可无限期延长初次心脏移植的存活时间（>140天），并可接受二次供体特异性（而非第三方）移植物（P<0.001）。接受来自耐受大鼠而非对照大鼠脾细胞的未致敏照射PVG大鼠接受了RA心脏移植，表明同种异体移植受体中存在调节性细胞。尽管具有耐受性，但在第90天，接受DSBT治疗的大鼠仍表现出慢性排斥反应的典型特征（血管闭塞率=77%；与同基因大鼠血管闭塞率=4%相比，P<0.001）。在第30天观察到明显的Th2偏移，尤其是移植物内白细胞介素（IL）-4的产生。与这种Th2偏移同时，移植物中出现了B细胞，并观察到IgG1（依赖Th2）的内皮沉积和C3结合。
在初次和二次移植物中防止移植物因急性排斥反应而丧失的调节性细胞，并不能预防慢性排斥反应的发生。
