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全身放射或放射（化疗）治疗胸部相关肿瘤的剂量限制性副作用。据推测，常驻细胞、免疫细胞和可溶性介质之间的复杂网络促进了肺组织中观察到的炎症和纤维化改变。炎症/纤维化的潜在机制仍不完全清楚，没有有效的治疗方法。自己的研究证实了白细胞室的变化，在3-30周后，在照射诱导的肺病的小鼠模型。有趣的是，我们最近首次证明了调节性T细胞（Treg）分别在炎症期（3周）和纤维化期（24-30周）的双相增加。进一步的初步数据显示，Treg表面标志物神经纤毛蛋白-1（NRP-1）在纤维化阶段上调。更重要的是，特异性敲除CD 4+细胞中的NRP-1，特别是Treg，显著减弱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（TGF）-β或在其细胞表面上结合活性TGF-β，预期Treg促进纤维化发展。此外，我们可以表明在纤维化阶段开始时Treg的消耗显著减少了纤维化。该项目旨在获得Treg在辐射诱导的纤维化发病机制中的作用的详细机制的理解。我们还将测试在辐射诱导的纤维化期间NRP-1的药理学抑制是否适合于减弱辐射诱导的肺纤维化。这些实验将揭示Treg的缺乏或免疫操纵是否可以用作预防或治疗辐射诱导的肺病的新治疗方法。

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.