Department of General Thoracic Surgery, University Hospital Bern, Bern, Switzerland.
Department of General Thoracic Surgery and Lung Transplantation, Pomeranian Medical University, Szczecin, Poland.
Eur J Cardiothorac Surg. 2018 Jan 1;53(1):194-200. doi: 10.1093/ejcts/ezx257.
The aim of this study was to investigate new therapeutic options to attenuate acute rejection in a rat lung allograft model. Cell-based gene therapies have recently been reported as a novel curative option in acute and chronic diseases for which conventional treatments are not available. We studied the effect of human interleukin 10 (hIL-10) on expressing bone marrow-derived mesenchymal stem cells (BMSCs) in combination with cyclosporine A (CsA) on acute rejection of lung allografts in the rat.
Lung allotransplantation was performed from male Brown Norway donor to male Fisher (F344) rats. Rat BMSCs were transfected with hIL-10 in vitro and introduced in the graft prior to implantation. Group A (n = 5) received CsA intraperitoneally (2.5 mg/kg body weight) for 5 days post-transplant; Group B (n = 5) received BMSC and CsA and Group C (n = 5) received hIL-10-BMSC before implantation and CsA. Graft function was assessed by blood gas levels only from the graft on day 5; tissue was sampled for histological grading of rejection and measurement of the wet-to-dry ratio.
All Group A control animals showed severe signs of rejection. On Day 5, all grafts in Group C showed improved gas exchange (mean arterial partial pressure of oxygen 222.2 ± 40.38 mmHg vs 92.36 ± 20.92 mmHg in Group B and 42.72 ± 18.07 mmHg in Group A). Histological examination revealed moderate-to-severe rejection in all animals in Group A [International Society for Heart and Lung Transplantation Level III B (ISHLT)] in contrast to low-to-moderate rejection in Group B (II-IIIA) and much improved histological grade in Group C (I-IIA). Moreover, the wet-to-dry ratio was also reduced in Group C (4.8 ± 1.19 compared with 4.78 ± 0.62 in Group B and 9.36 ± 0.90 in Group A).
The hIL-10 BMSC represent a promising novel method for localized cell-based gene therapy for acute rejection in a rat lung allograft model.
本研究旨在探讨一种新的治疗方法，以减轻大鼠肺移植模型中的急性排斥反应。细胞基因治疗最近被报道为一种新的治疗方法，可用于治疗传统治疗方法无效的急性和慢性疾病。我们研究了人白细胞介素 10（hIL-10）联合环孢素 A（CsA）对表达骨髓间充质干细胞（BMSCs）的大鼠肺同种异体移植物急性排斥反应的影响。
将雄性布朗-挪威供体的肺移植到雄性 Fisher（F344）大鼠体内。体外转染大鼠 BMSCs 表达 hIL-10，移植前将其引入移植物。A 组（n=5）术后腹腔内给予 CsA（2.5mg/kg 体重）5 天；B 组（n=5）接受 BMSC 和 CsA；C 组（n=5）在移植前给予 hIL-10-BMSC 和 CsA。仅通过移植物在第 5 天评估移植物的血气水平；取样组织进行排斥反应的组织学分级和湿重-干重比的测量。
所有 A 组对照动物均表现出严重的排斥反应迹象。第 5 天，C 组所有移植物的气体交换均得到改善（平均动脉部分氧分压 222.2±40.38mmHg 与 B 组 92.36±20.92mmHg 和 A 组 42.72±18.07mmHg）。组织学检查显示，A 组所有动物均出现中重度排斥反应[国际心肺移植学会（ISHLT）III B 级]，而 B 组为低-中度排斥反应（II-IIIA），C 组的组织学分级明显改善（I-IIA）。此外，C 组的湿重-干重比也降低（4.8±1.19 与 B 组 4.78±0.62 和 A 组 9.36±0.90）。
hIL-10 BMSC 是一种有前途的新型方法，可用于大鼠肺移植模型中的急性排斥反应的局部细胞基因治疗。
