1 Institute of Organ Transplantation, Changzheng Hospital, Shanghai, China. 2 National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China. 3 Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. 4 Department of Urology, General Hospital of Lanzhou Military Region, Lanzhou, China. 5 Address correspondence to: Prof. Quan-xing Wang, National Key Laboratory of Medical Immunology, Second Military Medical University or Prof. Liming Wang, Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Transplantation. 2013 Sep;96(6):529-37. doi: 10.1097/TP.0b013e31829b7bfc.
Antibody-mediated rejection (AMR) is gaining increasing recognition as a critical causative factor contributing to graft loss in organ transplantation. However, current therapeutic options for prevention and treatment of AMR are very limited and ineffective. The impact of epigenetic modification in B-cell function and its involvement in AMR is still yet to be explored.
The impacts of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on isolated murine B-cell viability, proliferation, apoptosis, expression of surface marker, and secretion of immunoglobulin and interleukin-10 were investigated. In vivo, a murine cardiac transplant model was used to evaluate the effect of SAHA on splenic B-cell subsets and on AMR in Rag1(-/-) recipient mice after reconstitution of allostimulated B cells.
SAHA possesses capability to repress B-cell function. Specifically, SAHA is potent to decrease the viability of isolated B cells by inducing apoptosis. SAHA was also found capable of suppressing the expression of B-cell costimulatory molecules and, as a result, addition of SAHA into the cultures attenuated B-cell proliferation and immunoglobulin secretion. In line with these results, administration of SAHA significantly suppressed AMR in Rag1(-/-) recipient mice after reconstitution of allostimulated B cells along with enhanced cardiac allograft survival time. Mechanistic studies revealed that SAHA promotes B-cell secretion of interleukin-10.
Our data support that SAHA could be a promising immunosuppressive agent with potential beneficial effect on prevention and treatment of AMR.
抗体介导的排斥反应（AMR）作为导致器官移植中移植物丢失的一个关键致病因素，正受到越来越多的关注。然而，目前预防和治疗 AMR 的治疗选择非常有限且无效。B 细胞功能的表观遗传修饰及其在 AMR 中的作用仍有待探索。
研究了组蛋白去乙酰化酶抑制剂（SAHA）对分离的鼠 B 细胞活力、增殖、凋亡、表面标记表达和免疫球蛋白及白细胞介素-10 分泌的影响。在体内，使用鼠心脏移植模型评估 SAHA 对 Rag1(-/-)受体小鼠脾 B 细胞亚群和同种刺激 B 细胞重建后 AMR 的影响。
SAHA 具有抑制 B 细胞功能的能力。具体而言，SAHA 通过诱导细胞凋亡来降低分离的 B 细胞的活力。还发现 SAHA 能够抑制 B 细胞共刺激分子的表达，因此，在培养物中添加 SAHA 会减弱 B 细胞的增殖和免疫球蛋白分泌。与这些结果一致的是，在同种刺激 B 细胞重建后，SAHA 显著抑制 Rag1(-/-)受体小鼠的 AMR，并延长心脏移植物的存活时间。机制研究表明，SAHA 可促进 B 细胞分泌白细胞介素-10。
我们的数据支持 SAHA 可能是一种有前途的免疫抑制剂，对预防和治疗 AMR 具有潜在的有益作用。
