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

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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.