Background

In human lung transplant recipients, a decline in club cell secretory protein (CCSP) in bronchoalveolar lavage fluid has been associated with chronic lung allograft dysfunction (CLAD) as well as the induction of exosomes and immune responses that lead to CLAD. However, the mechanisms by which CCSP decline contributes to CLAD remain unknown.

Methods

To define the mechanisms leading to CCSP decline and chronic rejection, we employed two mouse models: 1) chronic rejection after orthotopic single lung transplantation and 2) anti-major histocompatibility complex (MHC) class I–induced obliterative airway disease.

Results

In the chronic rejection mouse model, we detected circulating exosomes with donor MHC (H2^b) and lung self-antigens and also development of antibodies to H2^b and lung self-antigens and then a decline in CCSP. Furthermore, DBA2 mice that received injections of these exosomes developed antibodies to donor MHC and lung self-antigens. In the chronic rejection mouse model, natural killer (NK) and CD8 T cells were the predominant graft-infiltrating cells on day 14 of rejection followed by exosomes containing NK cell–associated and cytotoxic molecules on day 14 and 28. When NK cells were depleted, exosomes with NK cell–associated and cytotoxic molecules as well as fibrosis decreased.

Conclusions

Induction of exosomes led to immune responses to donor MHC and lung self-antigens, resulting in CCSP decline, leading to NK cell infiltration and release of exosomes from NK cells. These results suggest a novel role for exosomes derived from NK cells in the pathogenesis of chronic lung allograft rejection.

中文翻译：

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肺移植中俱乐部细胞分泌蛋白的下降与导致慢性排斥反应的自然杀伤细胞外泌体的释放有关

 背景

在人肺移植受者中，支气管肺泡灌洗液中俱乐部细胞分泌蛋白（CCSP）的下降与慢性肺同种异体移植功能障碍（CLAD）以及导致 CLAD 的外泌体和免疫反应的诱导有关。然而，CCSP 下降导致 CLAD 的机制仍不清楚。

 方法

为了确定导致 CCSP 下降和慢性排斥的机制，我们采用了两种小鼠模型：1）原位单肺移植后慢性排斥和 2）抗主要组织相容性复合体（MHC）I 类诱导的闭塞性气道疾病。

 结果

在慢性排斥小鼠模型中，我们检测到具有供体 MHC (H2 ^b ) 和肺自身抗原的循环外泌体，并且还产生了针对 H2 ^b和肺自身抗原的抗体，然后 CCSP 下降。此外，接受这些外泌体注射的 DBA2 小鼠产生了针对供体 MHC 和肺自身抗原的抗体。在慢性排斥小鼠模型中，自然杀伤 (NK) 和 CD8 T 细胞是排斥第 14 天的主要移植物浸润细胞，随后是第 14 天和第 28 天含有 NK 细胞相关分子和细胞毒性分子的外泌体。 ，带有 NK 细胞相关分子和细胞毒性分子的外泌体以及纤维化减少。

 结论

外泌体的诱导导致对供体 MHC 和肺自身抗原的免疫反应，导致 CCSP 下降，导致 NK 细胞浸润并从 NK 细胞中释放外泌体。这些结果表明源自 NK 细胞的外泌体在慢性肺同种异体移植排斥的发病机制中具有新的作用。