MONOCYTE/ENDOTHELIAL INTERACTIONS--MONOCYTE ACTIVATION

系统性硬化/硬皮病是一种未知的慢性自身免疫性疾病 病因学，特征是细胞介导的免疫改变，在 自身抗体的产生和胶原蛋白的过度沉积 内脏和皮肤。人类疾病很难研究，因为早期 变化是微妙的，诊断经常被推迟，现有的小鼠 硬皮病模型在研究硬皮病的有效性方面是有限的。 复杂的免疫异常。来自体外和体内工作的证据 硬皮病肺部病变提示TGFbeta1产生 通过真皮血管周围室中激活的单核细胞是一种有效的 刺激成纤维细胞上调胶原基因，导致 纤维化症。假设：真皮血管周围皮肤单核细胞激活 分室和分化为产生TGFbeta1的细胞是至关重要的 早期硬皮病的事件。我在两只小鼠身上研究了这些事件 硬皮瘤性移植物抗宿主病(GVHD)模型[(C57BL/6J至 Lp/J)和(B10.D2至Balb/c)]，其中动物发生GVHD，皮肤 骨髓移植后的增厚和自身抗体 次要组织亲和性基因座。接受互换骨骼的对照组小鼠 骨髓移植(LP/6至C/57BL/6J)发展为移植物抗宿主病和真皮移植 单个核细胞浸润，但不会发展成皮肤增厚。目标 I：确定皮肤早期危重事件的顺序 硬皮病型移植物抗宿主病动物皮肤微血管间隔的研究 为了更好地了解硬皮病的病理生理学 并制定新的有针对性的干预措施。原位杂交 和免疫染色研究，以确定激活的时间进程 内皮、单核细胞的流入和转化生长因子β1的产生将提供 为有针对性的活体干预奠定基础。目标II：在活体内使用 检测特定细胞因子(TGFbeta1)和 硬皮病的细胞类型(单核/巨噬细胞)。能不能 单核/巨噬细胞导向治疗可抑制硬化过程？ 注射抗单核细胞表面分子(Mac-1，LFA-1， VLA-4)和产物(TGFbeta1)在体内通过微渗泵提供了一种 一种可以操纵变量以检验以下假设的系统 单核细胞转化生长因子β1的产生在骨肉瘤的发生和发展中起关键作用 纤维化症。确定硬皮病的主要早期免疫事件将 提供了一种在体内测试创新免疫疗法的手段。

Systemic sclerosis/scleroderma is a chronic autoimmune disease of unknown etiology, characterized by altered cell-mediated immunity, in the production of autoantibodies, and the excessive deposition of collagen in viscerae and skin. Human disease is difficult to study because the early changes are subtle and diagnosis is often delayed, and existing murine models for scleroderma are limited in their usefulness for study of the complex immunologic abnormalities. Evidence from in vitro and in vivo work on pulmonary lesions in human scleroderma suggests that TGFbeta1 produced by activated monocytes in dermal perivascular compartments is a potent stimulus for collagen gene up-regulation by fibroblasts, leading to fibrosis. Hypothesis: cutaneous monocyte activation in dermal perivascular compartments and differentiation to TGFbeta1-producing cells are critical events in early scleroderma. In am studying these events in two murine sclerodermatous graft-versus-host disease (GVHD) models [(C57BL/6J to LP/J) and (B10.D2 to Balb/c)] in which animals develop GVHD, skin thickening and autoantibodies after bone marrow transplantation across minor histocompatibility loci. Control mice receiving the reciprocal bone marrow transplantation (LP/6 to C/57BL/6J) develop GVHD and dermal mononuclear cell infiltrates, but do not develop the skin thickening. Aim I: To determine the sequence of early critical events in the dermal microvascular compartment in skin of animals with sclerodermatous GVHD in order to better understand the pathophysiology for sclerodermatous disease, and to devise novel focused interventions. In situ hybridization and immunostaining studies to establish the time course of activation of endothelium, influx of monocytes, and production of TGFbeta1 will provide a foundation for focused in vivo interventions. Aim II: To employ in vivo interventions testing involvement of specific cytokines (TGFbeta1) and cell types (monocyte/macrophages) in sclerodermatous disease. Can the sclerotic process be inhibited using monocyte/macrophage-directed therapy? Infusion of antibodies against monocyte surface molecules (Mac-1, LFA-1, VLA-4) and products (TGFbeta1) by miniosmotic pumps in vivo provides a system in which variables can be manipulated to test the hypothesis that monocyte TGFbeta1 production is critical to initiation and progression of fibrosis. Identifying major early immunologic events in scleroderma will provide a means to test innovative immunotherapies in vivo.