Regulation of pulmonary fibrosis by CD4+T cells

纤维化是许多肺部疾病的共同最终途径， 结节病、石棉沉着病、类风湿性关节炎、硬皮病和特发性肺纤维化。虽然 肺纤维化似乎是慢性持续免疫激活的最终结果， 炎症过程的激发剂和驱动纤维化反应的精确因子都是已知的。在 在人类中，肺纤维化与实质和肺泡空间中的淋巴细胞浸润有关。 然而，这些细胞在疾病过程中的确切作用尚未确定。也就是说， 如果淋巴细胞参与加速纤维化，则是不堪重负的抗纤维化负饲料的一部分 回圈或两者。在这个提议中，使用一种独特的选择性缺失CD 4 + T细胞效应子的小鼠模型， 亚群，我们将测试的假设，即T辅助细胞发挥关键作用的调制肺 纤维化在目标1中，我们将确定Thi、Th 2、Th 17和调节性T细胞在免疫调节中的作用和机制。 加速或阻止纤维化的发展。在目标2中，我们将确定交替激活的 巨噬细胞（AAM）。这种相对较新的巨噬细胞亚群由Th 2细胞因子IL-4/IL-13诱导 因此我们认为Th 2 T细胞部分通过AAM的产生促进纤维化。在目标3中， 使用调节T效应子应答的试剂（TLR激动剂LPS和活病毒疫苗）来测试 假设体内T辅助细胞应答的偏斜可以用作一种新的治疗策略来治疗 或预防肺纤维化。

Fibrosis is the common final pathway for a number of pulmonary disorders such as sarcoidosis, asbestosis, rheumatoid arthritis, scleroderma and idiopathic pulmonary fibrosis. Although pulmonary fibrosis appears to be the end result of chronic unremitting immune activation, often neither the inciting agents of the inflammatory process nor the precise factors driving the fibrotic response are known. In humans, pulmonary fibrosis is associated with lymphocyte infiltration in the parenchyma and alveolar space. However, the precise role of these cells in the disease process has yet to be established. That is, it is unclear if the lymphocytes participate in accelerating fibrosis, are part of an overwhelmed anti-fibrotic negative feed back loop, or both. In this proposal, using a unique mouse model of selective deletion of CD4+ T cell effector subsets, we will test the hypothesis that T helper cells play a critical role in the modulation of pulmonary fibrosis. In Aim 1 we will determine the role and mechanism by which Thi, Th2, Th17 and regulatory T cells accelerate or prevent the development of fibrosis. In Aim 2 we will determine the role of alternatively activated macrophages (AAMs). This relatively new subset of macrophages is induced by the Th2 cytokines IL-4/IL-13 and thus we propose that Th2 T cells promote fibrosis in part through the generation of AAM. In Aim 3 we will employ agents to modulate the T effector response (the TLR agonist LPS and a live viral vaccine) to test the hypothesis that in vivo skewing of T helper responses can be employed as a novel therapeutic strategy to treat or prevent lung fibrosis.