Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria.
Front Immunol. 2022 Dec 8;13:1060576. doi: 10.3389/fimmu.2022.1060576. eCollection 2022.
In kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model.
Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period.
Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.
在肾移植中，与钙调磷酸酶抑制剂治疗相比，CTLA4-Ig 融合蛋白贝伐单抗可改善移植物功能，但也会增加急性排斥反应的风险。与第二种共刺激阻断剂联合使用可能会改善结果，同时避免钙调磷酸酶抑制剂的毒性。本研究的目的是在严格的小鼠心脏移植模型中确定 CTLA4-Ig 和 CD40L 阻断联合使用导致无排斥反应的永久性移植物存活的条件。
接受过完全错配 BALB/c 心脏同种异体移植的野生型或 CD40L（CD154）敲除小鼠。研究了 CTLA4-Ig 和阻断αCD40L 单克隆抗体（mAb）的诱导和维持方案。在 100 天的随访期间评估移植物存活、排斥严重程度和供体特异性抗体（DSA）的形成。
在移植时单独使用αCD40L mAb 作为单一疗法可显著延长心脏移植物的存活时间，但当与慢性 CTLA4-Ig 治疗联合使用时，并未进一步改善结果（可将移植物存活时间延长至中位数 22 天）。同样，慢性αCD40L mAb 治疗（0.5mg）与围手术期 CTLA4-Ig 联合使用，尽管消除了 DSA 的形成，但在一部分小鼠中仍导致排斥反应和广泛的组织学损伤。只有通过使用 CD40L 受体小鼠或慢性αCD40L 给药永久中断 CD40-CD40L 信号，才能与慢性 CTLA4-Ig 协同作用，在所有受者中实现长期的同种异体移植物存活，并保持组织学移植物完整性，而不形成 DSA。当两种治疗药物均长期给药时，α-CD40L 和 CTLA4-Ig 的联合使用效果最佳。
