INTEGRIN-DEPENDENT T CELL-MEDIATED MECHANISMS OF PULMONARY FIBROSIS

描述（由申请人提供）：肺纤维化是自身免疫性风湿性疾病（如硬皮病、类风湿性关节炎、皮肌炎和多发性肌炎）患者致残和死亡的主要原因。肺纤维化的机制是复杂的，知之甚少，现代治疗是完全不足的。纤维化的严重程度和随后的肺功能下降通常与T淋巴细胞的肺积聚有关，尽管T细胞促进纤维化的机制仍有争议。我们的观察表明，CC趋化因子CCL18在肺纤维化T淋巴细胞和纤维化的积聚中可能起着核心作用。本研究的具体目的是研究肺T淋巴细胞的表型和促纤维化作用的机制，并研究CCL18是否可以直接使正常人肺T细胞的表型向促纤维化方向倾斜。总体假设是肺纤维化是treg介导的过度免疫抑制和抗炎反应的一部分。本研究的特异性假设是肺T细胞由于其调节性表型（Treg）而促进纤维化。具体来说，我们假设这些肺T细胞是TGF-¿+，类似于Th3和Tregs通过膜结合TGF-¿起作用。我们进一步假设，这些细胞以整合素依赖的方式持续存在于肺中，通过整合素依赖的机制分泌和激活TGF-¿，在细胞表面保留TGF-¿，并最终通过可溶性和膜结合的TGF-¿刺激成纤维细胞，从而促进肺纤维化。为了评估这一假设的有效性，将解决以下具体目标：

DESCRIPTION (provided by applicant): Pulmonary fibrosis is a major cause of disability and death in patients with autoimmune rheumatic diseases such as scleroderma, rheumatoid arthritis, dermatomyositis and polymyositis. The mechanisms of lung fibrosis are complex and poorly understood, and modern therapies are utterly inadequate. The severity of fibrosis and subsequent decline in lung function are frequently associated with pulmonary accumulation of T lymphocytes, although the mechanisms by which T cells promote fibrosis remain controversial. Our observations point to a possible central role of a CC chemokine CCL18 in pulmonary accumulation of profibrotic T lymphocytes and fibrosis. The Specific Objective of this study is to investigate the phenotypes and the mechanisms of the profibrotic action of pulmonary T lymphocytes, and to investigate whether CCL18 can directly skew the phenotype of normal human pulmonary T cells toward profibrotic. The Overall Hypothesis is that pulmonary fibrosis is part of an exaggerated Treg-mediated immunosuppressive and anti-inflammatory response. The Specific Hypothesis of this study is that pulmonary T cells promote fibrosis because of their regulatory phenotype (Treg). Specifically, we hypothesize that these pulmonary T cells are TGF-¿+, similar to Th3 and Tregs acting through membrane-bound TGF-¿. We further hypothesize that these cells facilitate pulmonary fibrosis by persisting in the lung in an integrin-dependent fashion, secreting and activating TGF-¿ through integrin-dependent mechanisms, retaining TGF-¿ on the cell surface, and ultimately stimulating fibroblasts through soluble and membrane-bound TGF-¿. To evaluate the validity of this hypothesis, the following Specific Aims will be addressed: 1. Define the profibrotic phenotype of pulmonary T lymphocytes leading to their prolonged persistence in the lungs and increased production, activation, and cell surface binding of TGF-¿ in the CCL18 pulmonary overexpression model, with a specific focus on the expression profile and role of integrins. 2. Determine whether aV-containing and ¿2-containing integrins facilitate cell-cell interactions between pulmonary T cell and fibroblasts, the increase in TGF-¿ production and/or activation, cell surface binding of TGF-¿ by T cells, and stimulation of collagen production by fibroblasts. 3. Investigate the ability of CCL18 to directly modulate the phenotype of pulmonary T cells toward profibrotic, by stimulating the expression, activation, and cell surface binding of TGF-¿, and expression of aV- containing and ¿2-containing integrins. The results of this study may identify T lymphocytes and CCL18 as targets for future antifibrotic therapies in patients with autoimmune rheumatic diseases.