Latner Thoracic Research Laboratories, University Health Network, Canada; Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Latner Thoracic Research Laboratories, University Health Network, Canada; Division of Respirology, Department of Medicine, University of Toronto, Canada.
Transpl Immunol. 2021 Dec;69:101467. doi: 10.1016/j.trim.2021.101467. Epub 2021 Sep 20.
IL-17A is implicated in the pathogenesis of chronic lung allograft dysfunction, which limits survival after lung transplantation. While many cells express the IL-17 receptor A (IL-17RA) which is the main receptor for IL-17A, the cellular targets of IL-17A in development of post-transplant fibrosis are unknown. The purpose of this study was to determine whether IL-17RA expression by donor or recipient structural or bone marrow (BM) cells is required for the development of allograft fibrosis in a mouse intrapulmonary tracheal transplantation (IPTT) model. BM chimeras were generated using C57BL/6 and IL-17RA-knockout mice. After engraftment, allogeneic IPTTs were performed using the chimeric and BALB/c mice as donors or recipients. This allowed us to assess the effect of IL-17RA deficiency in recipient BM, recipient structural, donor BM, or donor structural compartments separately. Tracheal grafts, the surrounding lung, and mediastinal lymph nodes were assessed 28 days after IPTT. Only recipient BM IL-17RA deficiency resulted in attenuation of tracheal graft obliteration. In the setting of recipient BM IL-17RA deficiency, T cells and neutrophils were decreased in mediastinal lymph nodes. Additionally, recipient BM IL-17RA deficiency was associated with increased B220PNAd lymphoid aggregates, consistent with tertiary lymphoid organs, in proximity to the tracheal allograft. In this IPTT model, recipient BM-derived cells appear to be the primary targets of IL-17RA signaling during fibrotic obliteration of the tracheal allograft.
IL-17A 参与慢性肺移植物功能障碍的发病机制，限制了肺移植后的生存。虽然许多细胞表达 IL-17 受体 A（IL-17RA），这是 IL-17A 的主要受体，但在移植后纤维化的发展中，IL-17A 的细胞靶标尚不清楚。本研究的目的是确定供体或受体结构或骨髓（BM）细胞中 IL-17RA 的表达是否是小鼠肺内气管移植（IPTT）模型中同种异体移植纤维化发展所必需的。使用 C57BL/6 和 IL-17RA 敲除小鼠生成 BM 嵌合体。在植入后，使用嵌合体和 BALB/c 小鼠作为供体或受体进行同种异体 IPTT。这使我们能够分别评估受体 BM、受体结构、供体 BM 或供体结构区中 IL-17RA 缺陷的影响。在 IPTT 后 28 天评估气管移植物、周围肺和纵隔淋巴结。只有受体 BM 中的 IL-17RA 缺陷导致气管移植物闭塞减弱。在受体 BM 中 IL-17RA 缺陷的情况下，纵隔淋巴结中的 T 细胞和中性粒细胞减少。此外，受体 BM 中的 IL-17RA 缺陷与靠近气管同种异体移植物的 B220PNAd 淋巴样聚集物（与三级淋巴器官一致）增加有关。在这个 IPTT 模型中，受体 BM 来源的细胞似乎是 IL-17RA 信号在气管同种异体纤维化闭塞过程中的主要靶标。
