Misumi Keizo, Wheeler David S, Aoki Yoshiro, Combs Michael P, Braeuer Russell R, Higashikubo Ryuji, Li Wenjun, Kreisel Daniel, Vittal Ragini, Myers Jeffrey, Lagstein Amir, Walker Natalie M, Farver Carol F, Lama Vibha N
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA.
JCI Insight. 2020 Dec 3;5(23):136533. doi: 10.1172/jci.insight.136533.
Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 → parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into μMt-/- (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory μ-chain (μs) double-KO (AID-/-μs-/-) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.
了解导致同种异体移植纤维化和慢性移植失败的不同致病机制是改善实体器官移植后预后的关键。在此，我们描述了一种限制性同种异体移植综合征（RAS）的F1→亲本位肺移植模型，RAS是慢性肺同种异体移植功能障碍（CLAD）的一种特别暴发性形式，并确定了体液免疫反应在RAS发展中的必要致病作用。将B6D2F1/J（H2-b/d）供体肺移植到亲代C57BL/6J（H2-b）受体中，表现出一系列组织病理学变化，从淋巴细胞浸润、纤维蛋白渗出和血管内皮炎到支气管周围和胸膜实质纤维化，类似于人类RAS肺中观察到的变化。基因表达谱分析显示，体液免疫细胞的差异激活是RAS小鼠模型的一个关键特征，在RAS肺同种异体移植中观察到显著的B细胞和浆细胞浸润。将B6D2F1/J肺同种异体移植到μMt-/-（成熟B细胞缺陷）或激活诱导的胞苷脱氨酶（AID）/分泌型μ链（μs）双敲除（AID-/-μs-/-）的C57BL/6J小鼠中，同种异体移植纤维化显著减少，表明B细胞分泌抗体在介导RAS病理过程中起关键作用。我们的研究表明，免疫反应的偏差决定了不同的同种异体移植重塑模式，并强调需要针对特定的CLAD表型开发靶向治疗方法。
