T CELL ADHESION MOLECULES IN MURINE LUPUS PNEUMONITIS

系统性红斑狼疮（SLE）的肺部受累很常见， 通常会使人丧失能力，偶尔也会致命 目前的治疗方法是 对肺部受累的疗效低于对其他器官系统的疗效。 为了确定SLE的分子发病机制，我们开发了一种小鼠 依赖于同基因激活的过继转移的模型系统 用DNA甲基转移酶（DNA MTase）抑制剂处理的CD 4 + T细胞 如普鲁卡因胺（Pca）。 正常AKR小鼠接受细胞的 用Pca处理的克隆T细胞系D10（D10 Pca）发育为 高滴度抗DNA自身抗体、肾炎、类似肝病 胆汁性肝硬化和淋巴间质性肺炎（LIP）。 脾切除术消除了除肺外所有器官的疾病活动， 表明该器官的病理学不依赖于自身抗体 生产 用DNA MTase抑制剂治疗增加表达 β 2整合素LFA-1（CD 11 a/CD 18）。 用CD 18转染的T细胞 也是自身反应性的，并在转移到同基因小鼠时诱导狼疮。 淋巴细胞DNA低甲基化和LFA-1过表达也可见 活动性狼疮患者 这些发现意味着T细胞 LFA-1的过度表达足以引发SLE，而T 细胞依赖性肺损伤可能是该过程的最早阶段。 这项建议将研究涉及肺的分子机制， 病理学在这个模型系统中，利用各种技术和 肺淋巴细胞其他模型研究的经验教训 贩卖人口 中心假设：LFA-1表达增加， 自身反应性T细胞介导与肺内皮细胞的粘附 以及肺抗原呈递细胞（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 相互作用启动其他活化T细胞向肺的募集 通过VLA-4/VCAM和选择素依赖性相互作用，诱导LIP。 具体目的1：验证是否需要D10 Pca的肺部定位 以诱导药物诱导的鼠LIP。具体目标2：确定 粘附相互作用介导D10 Pca和其他 肺淋巴细胞在LIP的发展。 具体目标3： 确定是否通过抑制D10 Pca的肺滞留 单克隆抗体（mAb）治疗可防止LIP的发展。 我们 长期目标是开发有效的治疗方法， SLE基于抗粘连策略。

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.