DENDRITIC CELL MODULATION OF AUTOREACTIVE T LYMPHOCYTES

提示存在寡克隆性或单克隆性T细胞增殖。 在多种自身免疫性和肿瘤性疾病的发病机制中。 在自身免疫和肿瘤疾病中。在自身免疫性疾病中 自身反应性T细胞可能直接导致组织损伤，或者它们 通过为自身反应性B细胞提供帮助而间接负责 分泌与组织损伤和/或功能障碍有关的自身抗体。 下调特定自身免疫反应的能力或消除 因此，一个特定的肿瘤T细胞克隆将是一个重要的 这些慢性病的治疗进展。我们已经确定了 参与细胞和分子相互作用的细胞和分子调控 人类自身反应性T和B细胞对DNA拓扑异构酶I(Topo I)的反应 系统性硬化症的主要自身抗原。我们的研究表明， 关于树突状细胞(DC)功能的最新数据 调节免疫反应表明成熟的DC是有效的抗原- 提呈细胞(APC)凭借其高组成表达 共刺激分子，尽管某些DC亚群T细胞 反应迟钝或容忍。在拟议的研究中，我们将研究 调节TOPO特异性自身反应性T细胞的两种途径 I：首先，我们计划使用树突状细胞作为有效的抗原递呈细胞 诱导产生TCR特异性(抗克隆)调节性T细胞的细胞 针对自身反应的TOPO I特异性T细胞；第二，我们计划 使用功能不成熟(即具有耐受性)的DC 修改DC以直接删除(通过细胞凋亡)或激活 自身反应性T细胞。这些研究将调查以下方法 自身反应性T细胞的体外消除和/或能量 为开发新型靶向免疫抑制药物奠定基础 自发性硬化症、其他自身免疫性疾病和恶性T细胞的治疗 精神错乱。

The presence of oligoclonal or monoclonal T cell expansion is implicated in the pathogenesis of a variety of autoimmune and neoplastic diseases. In autoimmune and neoplastic diseases. In autoimmune diseases the autoreactive T cells may be directly responsible for tissue damage or they have be indirectly responsible by providing help to autoreactive B cells to secrete autoantibodies involved in tissue damage and/or dysfunction. The ability to down modulate specific autoimmune responses or to eliminate a specific neoplastic T cell clone, therefore, would be an important advance in the therapy of these chronic illnesses. We have determined the cellular and molecular interactions involved in the regulation of the human autoreactive T and B cell responses to DNA topoisomerase I (topo I), a major autoantigen in systematic sclerosis. Our studies indicate that the Recent data concerning the functional capacity of dendritic cells (DCs) to regulate immune responses indicate that mature DC are potent antigen- presenting cells (APC) by virtue of their high constitutive expression of co-stimulatory molecules, although certain DC subsets T cell hyporesponsiveness or tolerance. In the proposed studies we will examine two approaches to the regulation of autoreactive T cells specific for topo I: first, we plan to use dendritic cells as potent antigen presenting cells to induce to TCR-specific (anti-clonotypic) regulatory T cells directed toward the autoreactive topo I-specific T cells; second, we plan to use functionally immature (i.e. tolerogenic) DCs and genetically modified DCs to directly delete (through apoptosis) or energize autoreactive T cells. These studies will investigate approaches for elimination and/or energy of the autoreactive T cells in vitro and will serve as the basis for the development of novel targeted immunosuppressive therapy for SSc, other autoimmune diseases, and malignant T cell disorders.