Pirenne Jacques, Kitade Hiroaki, Kawai Masaru, Koshiba Takaaki, Van Damme Boudewijn, Mathieu Chantal, Waer Mark
Abdominal Transplant Surgery, Katholieke Universiteit Leuven, Leuven, Belgium.
Transplantation. 2005 Feb 15;79(3 Suppl):S25-7. doi: 10.1097/01.tp.0000153295.51565.f1.
We developed a rodent model in which donor-specific blood transfusion (DSBT) promotes hyporesponsiveness and graft acceptance. In this model, signs of immune activation are present early posttransplant, with preserved proliferative responses against the donor and a dense cellular infiltrate in tolerant grafts. Intriguingly, an early accumulation of IFN-gamma is seen in grafts destined to become tolerized, supporting recent evidence that Th1 cytokines play a role in tolerance induction. Specific regulatory cells capable of propagating tolerance into naive recipients are operating. These mechanisms of immune activation and the generation of regulatory cells are influenced by immunosuppression (steroids and calcineurin inhibitors). In this model, in a second phase, a Th2 immune deviation occurs and is associated with the development of chronic rejection (vascular obliteration, endothelial IgG deposition, and complement binding). It remains unclear whether chronic rejection in this model is caused by Th2 type regulatory cells or whether chronic rejection is the consequence of an insufficient number of regulatory cells. In the clinic, the current strategy of profoundly inhibiting immune activation (in particular Th1 cytokines/responses) by using high dose calcineurin inhibitors and steroids may prove antagonistic with the development of tolerance, particularly when immunomodulatory strategies (such as DSBT) are applied. Development of chronic rejection in a regulation-based tolerance model suggests that deletion-based tolerogenic strategies may offer a more robust protection against chronic rejection.
我们建立了一种啮齿动物模型，其中供体特异性输血（DSBT）可促进低反应性和移植物接受。在该模型中，免疫激活的迹象在移植后早期就已出现，对供体的增殖反应得以保留，且耐受移植物中有密集的细胞浸润。有趣的是，在注定会产生耐受的移植物中可早期观察到干扰素-γ的积累，这支持了近期关于Th1细胞因子在耐受诱导中起作用的证据。能够将耐受性传递给未致敏受体的特定调节性细胞发挥着作用。这些免疫激活机制以及调节性细胞的产生受免疫抑制（类固醇和钙调神经磷酸酶抑制剂）影响。在该模型的第二阶段，会发生Th2免疫偏移，并与慢性排斥反应（血管闭塞、内皮IgG沉积和补体结合）的发展相关。目前尚不清楚该模型中的慢性排斥反应是由Th2型调节性细胞引起的，还是由于调节性细胞数量不足所致。在临床上，目前通过使用高剂量钙调神经磷酸酶抑制剂和类固醇来深度抑制免疫激活（特别是Th1细胞因子/反应）的策略，可能与耐受性的发展相互拮抗，尤其是在应用免疫调节策略（如DSBT）时。基于调节的耐受模型中慢性排斥反应的发生表明，基于清除的致耐受性策略可能对慢性排斥反应提供更强有力的保护。
