Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
Center for Life Science Research, University of Yamanashi, Chuo, Yamanashi, Japan.
Ann Thorac Cardiovasc Surg. 2021 Dec 20;27(6):355-365. doi: 10.5761/atcs.oa.20-00398. Epub 2021 May 12.
One of the serious problems after lung transplantation is chronic lung allograft dysfunction (CLAD). Most CLAD patients pathologically characterized by obliterative bronchiolitis (OB). Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-Ig is a combination protein of the Fc fragment of human IgG1 linked to the extracellular domain of CTLA4. The aim of the study was to examine the effect of CTLA4-Ig therapy on OB using a mouse intrapulmonary tracheal transplantation (IPTT) model.
IPTT was performed between BALB/c (donor) and C57BL/6 (recipient) mice. Abatacept, which is a commercially available form of CTLA4-Ig, was intraperitoneally injected in recipient mice immediately after surgery, on days 7, 14, and 21. The mice in the control group received human IgG.
We performed semi-quantitative analysis of graft luminal obliteration at post-transplant day 28. We calculated the obliteration ratio of the lumen of the transplanted trachea in each case. The obliteration ratio was significantly lower in the CTLA4-Ig group than that in the control group (91.2 ± 2.1% vs. 47.8 ± 7.9%, p = 0.0008). Immunofluorescent staining revealed significantly decreased lymphoid neogenesis in the lung.
CTLA4-Ig therapy attenuated tracheal obliteration with fibrous tissue in the mouse IPTT model. The attenuation of fibrous obliteration was correlated with the inhibition of lymphoid neogenesis.
肺移植后严重的问题之一是慢性肺移植物功能障碍（CLAD）。大多数 CLAD 患者的病理特征为闭塞性细支气管炎（OB）。细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）-Ig 是与人 IgG1 的 Fc 片段连接的 CTLA4 细胞外结构域的组合蛋白。本研究的目的是使用小鼠肺内气管移植（IPTT）模型检查 CTLA4-Ig 治疗对 OB 的影响。
在 BALB/c（供体）和 C57BL/6（受体）小鼠之间进行 IPTT。在手术后立即、第 7、14 和 21 天，通过腹腔内注射阿巴西普（一种市售的 CTLA4-Ig 形式）给受体小鼠。对照组小鼠接受人 IgG。
我们在移植后第 28 天对移植物管腔闭塞进行了半定量分析。我们计算了每个情况下移植气管管腔闭塞的闭塞率。CTLA4-Ig 组的闭塞率明显低于对照组（91.2±2.1%比 47.8±7.9%，p=0.0008）。免疫荧光染色显示肺内淋巴样新生明显减少。
CTLA4-Ig 治疗减轻了小鼠 IPTT 模型中气管的纤维组织闭塞。纤维闭塞的减轻与淋巴样新生的抑制有关。
