Department of General Surgery, Tianjin Medical University General Hospital, Tianjin General Surgery Institute, Tianjin, China,
Cardiovasc Drugs Ther. 2014 Apr;28(2):115-22. doi: 10.1007/s10557-013-6502-9.
Cardiac allograft vasculopathy (CAV) is a major complication limiting the long-term survival of cardiac transplants. The role of memory T cells (Tmem) in the pathogenesis of CAV remains elusive. This study investigated the role of Tmem cells in the development of CAV and the therapeutic potential of targeting the OX40/OX40L pathway for heart transplant survival.
Tmem cells were generated in Rag-1(-/-) C57BL/6 (B6) mice by homeostatic proliferation (HP) of CD40L null CD3(+) T cells from B6 mice. Rag-1(-/-) B6 mice (H-2(b)) harboring Tmem cells received cardiac allografts from BALB/c mice (H-2(d)), and were either untreated or treated with anti-OX40L monoclonal antibody (mAb) (0.5 mg/mouse/day) for 10 days.
Six weeks after HP, the majority of transferred CD40L(-/-) T cells in Rag-1(-/-) B6 mice were differentiated to CD44(high) and CD62L(low) Tmem cells. BALB/c heart allografts in Rag-1(-/-) B6 recipient mice in the presence of these Tmem cells developed a typical pathological feature of CAV; intimal thickening, 100 days after transplantation. However, functionally blocking the OX40/OX40L pathway with anti-OX40L mAb significantly prevented CAV development and reduced the Tmem cell population in recipient mice. Anti-OX40L mAb therapy also significantly decreased cellular infiltration and cytokine (IFN-γ, TNF-α and TGF-β) expression in heart allografts.
Tmem cells mediate CAV in heart transplants. Functionally blocking the OX40/OX40L pathway using anti-OX40L mAb therapy prevents Tmem cell-mediated CAV, suggesting therapeutic potential for disrupting OX40-OX40L signaling in order to prevent CAV in heart transplant patients.
心脏同种异体移植血管病（CAV）是限制心脏移植长期存活的主要并发症。记忆 T 细胞（Tmem）在 CAV 发病机制中的作用仍不清楚。本研究探讨了 Tmem 细胞在 CAV 发展中的作用以及针对 OX40/OX40L 通路靶向治疗以提高心脏移植存活率的潜力。
通过 Rag-1(-/-) C57BL/6（B6）小鼠中 CD40L 缺失 CD3(+)T 细胞的同源性增殖（HP）产生 Tmem 细胞，该细胞来自 B6 小鼠。携带 Tmem 细胞的 Rag-1(-/-)B6 小鼠（H-2(b)) 接受来自 BALB/c 小鼠（H-2(d)) 的心脏同种异体移植物，未治疗或用抗 OX40L 单克隆抗体（mAb）（0.5 mg/只/天）治疗 10 天。
HP 后 6 周，Rag-1(-/-)B6 小鼠中大多数转导的 CD40L(-/-)T 细胞分化为 CD44(high)和 CD62L(low)Tmem 细胞。在存在这些 Tmem 细胞的情况下，BALB/c 心脏同种异体移植物在 Rag-1(-/-)B6 受体小鼠中发生典型的 CAV 病理特征；移植后 100 天出现内膜增厚。然而，用抗 OX40L mAb 功能性阻断 OX40/OX40L 通路可显著防止 CAV 发生，并减少受体小鼠中的 Tmem 细胞群。抗 OX40L mAb 治疗还显著降低了心脏移植物中的细胞浸润和细胞因子（IFN-γ、TNF-α 和 TGF-β）表达。
Tmem 细胞介导心脏移植中的 CAV。用抗 OX40L mAb 治疗功能性阻断 OX40/OX40L 通路可防止 Tmem 细胞介导的 CAV，提示通过破坏 OX40-OX40L 信号来预防心脏移植患者 CAV 的治疗潜力。
