DENDRITIC CELL MODULATION OF AUTOREACTIVE T LYMPHOCYTES

寡克隆或单克隆T细胞扩增的存在与 在多种自身免疫性和肿瘤性疾病的发病机制中。 自身免疫性疾病和肿瘤性疾病。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， 通过为自身反应性B细胞提供帮助， 分泌参与组织损伤和/或功能障碍的自身抗体。 下调特异性自身免疫反应或消除 因此，一个特异性肿瘤性T细胞克隆将是一个重要的 这些慢性疾病的治疗进展。吾等已厘定 细胞和分子间的相互作用参与了 人自身反应性T和B细胞对DNA拓扑异构酶I（topo I）反应， 系统性硬化症中的一种主要自身抗原。我们的研究表明， 关于树突状细胞（DC）的功能能力的最新数据， 调节免疫应答表明成熟DC是有效抗原- 提呈细胞（APC）由于其高组成性表达 共刺激分子，虽然某些DC亚群T细胞 低反应性或耐受性。在拟议的研究中，我们将审查 两种调节拓扑异构酶特异性自身反应性T细胞的方法 I：首先，我们计划使用树突状细胞作为有效的抗原提呈细胞 细胞以诱导TCR特异性（抗克隆型）调节性T细胞 针对自身反应性拓扑I特异性T细胞;第二，我们计划 使用功能上不成熟的（即致耐受性的）DC和遗传上不成熟的（即致耐受性的）DC， 修饰的DC直接删除（通过凋亡）或激活 自身反应性T细胞这些研究将探讨 本发明的目的是提供体外自身反应性T细胞的清除和/或能量， 作为开发新型靶向免疫抑制剂的基础， SSc、其他自身免疫性疾病和恶性T细胞的治疗 紊乱

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.