The role of Neuropilin-1 and regulatory T cells as therapeutical targets in radiation-induced lung fibrosis

放射性肺炎和纤维化是胸部相关肿瘤的全身照射或放射(化疗)治疗的限量副作用。据推测，驻留细胞、免疫细胞和可溶性介质之间的复杂网络促进了所观察到的肺组织炎症和纤维化改变。炎症/纤维化的潜在机制仍不完全清楚，也没有有效的治疗方法。自己的研究证实，在辐射诱导的肺病小鼠模型中，在照射后3-30周，白细胞室发生了变化。有趣的是，我们最近首次证实了炎症期(3周)和纤维化期(24-30周)调节性T细胞(Treg)的双向增加。进一步的初步数据显示，Treg表面标志神经粘连蛋白-1(NRP-1)在纤维化期表达上调。更重要的是，特异性敲除CD4+细胞中的NRP-1，特别是Treg，显著减轻了辐射诱导的肺纤维化。由于它们能够产生最有效的促纤维化细胞因子转化生长因子-β或结合细胞表面活性的转化生长因子-β，Treg有望促进纤维化的发展。此外，我们可以证明，在纤维化期开始时耗尽Treg可以显著减少纤维化。这项拟议的项目旨在从机制上详细了解Treg在辐射诱导的纤维化发病机制中的作用。我们还将测试在辐射诱导的纤维化过程中抑制NRP-1的药理作用是否适合于减轻辐射诱导的肺纤维化。这些实验将揭示Treg的缺失或免疫操纵是否可以作为预防或治疗放射性肺疾病的一种新的治疗方法。

Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of total body irradiation or radio(chemo)therapy of thorax-associated neoplasms. It is assumed that a sophisticated network between resident cells, immune cells and soluble mediators promote the observed inflammatory and fibrotic alterations in the lung tissue. The underlying mechanisms of the inflammation/fibrosis remain incompletely understood and no effective treatment is available. Own investigations corroborate alterations in the leukocyte compartment at 3-30 weeks after irradiation in a murine model of radiation-induced pneumopathy. Interestingly, we recently demonstrated for the first time a biphasic increase of regulatory T cells (Treg) in the inflammatory phase (3 weeks) and in the fibrotic phase (24-30 weeks), respectively. Further preliminary data revealed that the Treg surface marker neuropilin-1 (NRP-1) is upregulated during the fibrotic phase. Even more important, specific knockout of NRP-1 in CD4+ cells, especially Treg, significantly attenuated radiation-induced lung fibrosis. Due to their ability to produce the most potent profibrotic cytokine transforming growth factor (TGF)-beta or bind active TGF-beta on their cell surface Treg are expected to promote fibrosis development. Moreover, we could show that depletion of Treg at the beginning of the fibrotic phase reduced fibrosis significantly. The proposed project aims to gain a detailed mechanistic understanding of the role of Treg in the pathogenesis of radiation-induced fibrosis. We will also test whether pharmacological inhibition of NRP-1 during radiation-induced fibrosis is suited to attenuate radiation-induced lung fibrosis. These experiments will reveal whether the absence or immunological manipulation of Treg can be used as a novel therapeutic approach for the prevention or treatment of radiation-induced lung disease.