Koenen Hans J P M, Fasse Esther, Joosten Irma
Department of Blood Transfusion and Transplantation Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Transplantation. 2005 Aug 27;80(4):522-9. doi: 10.1097/01.tp.0000172217.97072.54.
Costimulation blockade based tolerance-inducing therapies might be disrupted by adjunct conventional immunosuppressive drug use. In the current study, we evaluated the compatibility of various immunosuppressive agents on costimulation blockade-based immunosuppression and T-cell anergy induction of human alloreactive T-cells in vitro. T-cell anergy is crucial in transplantation tolerance.
T cell anergy was induced in human mixed lymphocyte cultures in vitro, by monoclonal antibodies directed against the costimulatory ligands CD40 and CD86. The effect of coadministration of conventional immunosuppressive drugs (CsA, rapamycin or FK506) on the inhibitory potential of costimulation blockade and the induction and maintenance of T cell anergy was analyzed.
We found that monoclonal antibodies against CD40 and CD86 and the simultaneous use of conventional immunosuppressive drugs resulted in strong immunosuppression of proliferation and cytokine production. Rapamycin, in contrast to FK506 and CsA, facilitated T-cell apoptosis. However, drug cotreatment prevented costimulation blockade induced T-cell anergy. Induction of human T-cell anergy in vitro required approximately 5 days of culture. Coadministration of drugs at day 5 after the start of mAb treatment, when anergy was established, did not increase the immunosuppressive effect of mAb treatment. But interestingly, in the majority of experiments, in contrast to rapamycin and FK506, CsA did not affect the anergic state when given after T-cell anergy induction. Moreover, the cell death facilitating potential of rapamycin vanished when used later after T-cell activation.
Timing and choice of conventional drug are crucial in the success of costimulation blockade-based tolerance induction therapies.
基于共刺激阻断的诱导耐受疗法可能会因同时使用传统免疫抑制药物而受到干扰。在本研究中，我们在体外评估了各种免疫抑制剂与基于共刺激阻断的免疫抑制以及人同种异体反应性T细胞的T细胞无反应性诱导之间的兼容性。T细胞无反应性在移植耐受中至关重要。
通过针对共刺激配体CD40和CD86的单克隆抗体在体外人混合淋巴细胞培养物中诱导T细胞无反应性。分析了传统免疫抑制药物（环孢素、雷帕霉素或他克莫司）联合使用对共刺激阻断的抑制潜力以及T细胞无反应性的诱导和维持的影响。
我们发现，针对CD40和CD86的单克隆抗体以及传统免疫抑制药物的同时使用导致对增殖和细胞因子产生的强烈免疫抑制。与他克莫司和环孢素相比，雷帕霉素促进T细胞凋亡。然而，药物联合治疗阻止了共刺激阻断诱导的T细胞无反应性。体外诱导人T细胞无反应性需要大约5天的培养时间。在单克隆抗体治疗开始后第5天（此时无反应性已建立）联合使用药物，并未增加单克隆抗体治疗的免疫抑制效果。但有趣的是，在大多数实验中，与雷帕霉素和他克莫司不同，环孢素在T细胞无反应性诱导后给予时不影响无反应状态。此外，雷帕霉素促进细胞死亡的潜力在T细胞活化后较晚使用时消失。
传统药物的使用时机和选择对于基于共刺激阻断的耐受诱导疗法的成功至关重要。
