T CELLS AND CYTOKINES IN PULMONARY FIBROSIS

描述(改编自申请人的摘要)：委托人 博莱霉素(BLM)是一种抗肿瘤抗生素，其作用是诱导 肺纤维化。利用已建立的博莱曼诱导的小鼠模型 对于肺纤维化，研究人员建议确定非T细胞的作用 细胞因子和T细胞在肺损伤诱导和维持中的作用 纤维化症。研究人员的初步数据表明，博莱姆诱导 B细胞和T细胞缺失的C57BL/6小鼠(SCID小鼠)的肺纤维化 (C57BL/6 SCID X CB.17 SCID)F1小鼠，而CB.17 SCID小鼠未见。最近， 研究人员证明，C57BL/6小鼠在其中肺纤维化 经气管插管(I.T.)BLM表现出明显的系统性 它们产生抗羊红细胞的能力受到抑制 斑块形成细胞的反应。博莱曼不会引起免疫抑制 SE是纤维化的一般结果，独立于 诱导肝纤维化的方法。关于这个的统一假设 认为博莱曼诱导的潜在细胞因子介导的事件启动 肺纤维化，也是免疫抑制的原因 与这种疾病有关。其目的是：1)调查 T细胞和非T细胞细胞因子在启动和维持博莱霉素中的作用 博莱霉素(BLM)诱导的小鼠肺纤维化。SCID小鼠及其胸腺 对应物将用于确定非T细胞细胞因子，这些细胞因子是 肝纤维化的发生发展与非T细胞的鉴别 T细胞是由T细胞介导的疾病相关成分。这个 博莱曼诱导的活性氧中间体在早期调控中的作用 将对促纤维化细胞因子进行分析，并对BLM诱导的小鼠产生抗药性 纤维化将被操纵，使其对博莱曼病易感，以便能够 确定与博莱姆敏感性有关的早期细胞因子事件。2)至 确定博莱曼诱导的免疫抑制的基础 肺纤维化。该假说认为博莱姆诱导的 Th1和Th2辅助T细胞群之间的平衡至少在一定程度上 负责免疫抑制的人将接受检测。由于转化生长因子-b、一氧化氮和干扰素-g 在博莱姆引起的肺纤维化期间被诱导，这些产品有 已经被证明是免疫抑制的，它们将作为起点 探讨免疫抑制的机制。

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.