T CELLS AND CYTOKINES IN PULMONARY FIBROSIS

描述（改编自申请人摘要）：主要方面 博来霉素（BLM），一种抗生素，的作用是诱导 肺纤维化 使用良好建立的BLM诱导的小鼠模型， 肺纤维化，研究人员建议确定非T细胞的作用， 细胞因子和T细胞在诱导和维持肺损伤中的作用 纤维化 研究人员的初步数据表明，BLM诱导 缺乏B和T细胞的C57 BL/6小鼠（SCID小鼠）的肺纤维化， （C57BL/6 SCID X CB. 17 SCID）F1小鼠，但在CB. 17 SCID小鼠中没有。 最近， 研究人员证明，C57BL/6小鼠肺纤维化， 用肠内愈合（i.t.）BLM表现出明显的全身性 抑制它们产生抗绵羊红细胞能力 空斑形成细胞反应。 免疫抑制不是由BLM引起的， SE和是纤维化的一般结果，并且独立于 诱导纤维化的方法。 这个统一的假设 提出BLM诱导的潜在的烟碱介导的事件启动 肺纤维化，也是免疫抑制， 与疾病有关 目的是：（1）探讨 T细胞和非T细胞细胞因子在博来霉素启动和维持中的作用 （BLM）诱导的小鼠肺纤维化。 SCID小鼠及其正常胸腺 对应物将用于确定非T细胞细胞因子， 重要的是纤维化的发展和区分非T细胞 T细胞介导的疾病相关成分。 的 BLM诱导的活性氧中间体在早期细胞凋亡调控中的作用 将分析促纤维化细胞因子，并且小鼠对BLM诱导的细胞因子具有抗性。 纤维化将被操纵，使他们BLM敏感，以便能够 以鉴定涉及BLM敏感性的早期细胞因子事件。 2)到 确定BLM诱导的免疫抑制的基础 肺纤维化 假设BLM诱导的改变， Th1和Th2辅助性T细胞群之间的平衡至少部分是 负责免疫抑制的人将进行测试。 由于TGF-β、NO和IFN-γ 在BLM引发的肺纤维化过程中诱导，这些产品具有 已被证明是免疫抑制，他们将作为起点， 研究免疫抑制的机制。

DESCRIPTION (Adapted from the applicant's abstract): The principal side effect of bleomycin (BLM), an antineoplastic antibiotic, is the induction of pulmonary fibrosis. Using the well established murine model of BLM-induced pulmonary fibrosis, the investigators propose to determine the role of non-T cell cytokines and T-cells in the induction and maintenance of pulmonary fibrosis. Preliminary data of the investigators indicate that BLM induces pulmonary fibrosis in C57BL/6 mice lacking B and T cells (SCID mice) and (C57BL/6 SCID X CB.17 SCID) F1 mice but not in CB.17 SCID mice. Recently, the investigators demonstrated that C57BL/6 mice in which pulmonary fibrosis was induced with intratracheal (i.t.) BLM exhibited marked systemic suppression in their ability to generate anti-sheep erythrocyte plaque-forming cell responses. Immunosuppression was not caused by BLM per se and was a general consequence of fibrosis and was independent of the method by which fibrosis was induced. The unifying hypothesis of this proposal is that underlying cytokine-mediated events induced by BLM initiate pulmonary fibrosis and are also responsible for the immunosuppression that is associated with the disorder. The aims are: 1) To investigate the role of T cell and non-T cell cytokines in initiating and maintaining bleomycin (BLM)-induced pulmonary fibrosis in mice. SCID mice and their euthymic counterparts will be used to determine the non-T cell cytokines which are important for the development of fibrosis and to differentiate the non-T cell mediated from the T cell associated components of the disease. The role of BLM-induced reactive oxygen intermediates in regulation of early profibrogenic cytokines will be analyzed and mice resistant to BLM-induced fibrosis will be manipulated to make them BLM-susceptible so as to be able to identify the early cytokine events involved in BLM-sensitivity. 2) To determine the basis of immunosuppression that is seen in BLM-induced pulmonary fibrosis. The hypothesis that BLM-induced alterations in the balance between Th1 and Th2 helper T cell populations is at least in part responsible for immunosuppression will be tested. Since TGF-b, NO and IFN-g are induced during BLM initiated pulmonary fibrosis and these products have been shown to be immunosuppressive they will serve as starting points to investigate the mechanism of immunosuppression.