T CELL ADHESION MOLECULES IN MURINE LUPUS PNEUMONITIS

系统性红斑狼疮(SLE)的肺部受累很常见， 通常使人丧失行为能力，有时甚至是致命的。目前的治疗方法是 对于肺部受累不如对其他器官系统有效。 为了明确系统性红斑狼疮的分子发病机制，我们研制了一种 依赖同基因激活的收养转移的模式体系 DNA甲基转移酶(DNA MTase)抑制剂对CD4+T细胞的作用 如普鲁卡因胺(PCA)。正常AKR小鼠接受细胞移植 经PCA(D10Pca)处理的克隆T细胞系D10的研制 高效价抗DNA自身抗体，肾炎，类似肝病 胆汁性肝硬化和淋巴样间质性肺炎(LIP)。 脾切除术消除了除肺部以外的所有器官的疾病活动， 表明该器官的病理不依赖于自身抗体。 制作。DNA MTase抑制剂治疗可增加基因表达 β2整合素LFA-1(CD11a/CD18)。CD18基因修饰的T细胞 也是自身反应性的，在转移到同基因小鼠时会诱发狼疮。 淋巴细胞DNA低甲基化和LFA-1过度表达也可见 在活动期狼疮患者中。这些发现表明T细胞 LFA-1的过度表达足以引发SLE，而T细胞 细胞依赖性肺损伤可能是这一过程的最早阶段。 这项建议将研究与肺相关的分子机制。 在这个模型系统中，利用各种技术和 从其他肺淋巴细胞模型的研究中学到的教训 贩卖人口。中心假说：LFA-1表达增加 自身反应性T细胞介导与肺内皮细胞的黏附 对肺抗原提呈细胞(APC)，特别是巨噬细胞 (Mphis)(导致细胞凋亡和自身抗原的释放)。这些 相互作用启动其他激活的T细胞向肺内的募集 通过VLA-4/VCAM和选择素依赖的相互作用，诱导LIP。 具体目标1：验证D10Pca的肺定位是必需的 诱导药物诱导的小鼠嘴唇。具体目标2：确定 黏附相互作用介导D10Pca及其他蛋白的肺定位 肺淋巴细胞在唇部发育中的作用。具体目标3： 确定是否通过抑制D10Pca的肺滞留 单抗(MAb)治疗可预防唇部发育。我们的 长期目标是开发有效的疗法来治疗已确诊的 基于防粘连策略的SLE。

Pulmonary involvement in systemic lupus erythematosus (SLE) is common, often incapacitating, and occasionally lethal. Current therapies are less effective for pulmonary involvement than for other organ systems. To define the molecular pathogenesis of SLE, we have developed a murine model system that depends on adoptive transfer of syngeneic activated CD4+ T cells treated with DNA methyltransferase (DNA MTase) inhibitors such as procainamide (Pca). Normal AKR mice receiving cells of the cloned T cell line D10 that have been treated with Pca (D10Pca) develop high-titer anti-DNA autoantibodies, nephritis, liver disease resembling biliary cirrhosis, and lymphoid interstitial pneumonitis (LIP). Splenectomy abrogates disease activity in all organs except the lungs, indicating that pathology in this organ does not depend of autoantibody production. Treatment with DNA MTase inhibitors increases expression of the Beta2 integrin LFA-1 (CD11a/CD18). T cells transfected with CD18 are also autoreactive and induce lupus on transfer to syngeneic mice. Lymphocyte DNA hypo-methylation and LFA-1 over-expression is also seen in patients with active lupus. These findings imply that T cell overexpression of LFA-1 is sufficient to initiate SLE, and that the T cell-dependent lung lesion may be the earliest stage in the process. This proposal will examine the molecular mechanisms involved in lung pathology in this model system, utilizing a variety of techniques and lessons learned from the study of other models of lung lymphocyte trafficking. Central Hypothesis: Increased LFA-1 expression by autoreactive T cells mediates adhesion both to lung endothelial cells and to lung antigen-presenting cells (APCs), especially macrophages (Mphis) (resulting in apoptosis and release of autoantigens). These interactions initiate recruitment of other activated T cells to the lung via VLA-4/VCAM and selectin-dependent interactions, inducing LIP. Specific Aim 1: To verify the lung localization of D10Pca is required to induce drug-induced murine LIP. Specific Aim 2: To determine the adhesive interactions mediating lung localization of D10Pca and other lung lymphocytes during development of LIP. Specific Aim 3: To determine whether inhibiting pulmonary retention of D10Pca via monoclonal antibody (mAb) treatment prevents development of LIP. Our long-term goal is to develop effective therapies to treat established SLE based on anti-adhesive strategies.