Generation of antigen specific regulatory T cells

描述（由申请人提供）：免疫抑制药物导致免疫反应的整体衰减，具有潜在的致命副作用，因此限制了其在治疗自身免疫性疾病中的应用。更有效的方法是抗原特异性灭活自身反应性T细胞。共刺激分子CTLA-4在诱导耐受性中的作用已被充分证实。尽管我们之前观察到显著的耐受性反应，但靶向递送CTLA-4信号有两个潜在的限制。首先是对某些大目标组织的有限可及性，其次是需要将抗ctla -4抗体与针对不同目标的不同组织特异性抗体连接起来。此外，这种策略可能对治疗全身自身免疫性疾病无效。为了克服这些潜在的限制，我们最近设计了一种新的策略，利用成熟树突状细胞（DC）作为apc，通过DC结合交联抗ctla -4抗体操纵免疫突触的相互作用，诱导调节性T细胞和对DC呈递的特定抗原的耐受性。该系统的主要优点是1)一个BiAb可以用来诱导对任何数量的抗原的耐受性；2)可用于T细胞对全身和器官特异性自身免疫性疾病自身抗原的耐受，也可诱导对过敏原、异体抗原和异种抗原等的耐受；3)体内注射dc可迁移至全身淋巴结构和靶器官，灭活抗原特异性T细胞；4)利用树突状细胞特殊的抗原呈递能力，诱导更强的调节性T细胞扩增和耐受性。

DESCRIPTION (provided by applicant): Immunosuppressive drugs result in global attenuation of the immune response with potential fatal side effects, thus, limiting their utility in treating autoimmune diseases. A more effective approach would involve antigen specific inactivation of autoreactive T cells. The role of the costimulatory molecule CTLA-4 in tolerance induction has been well documented. In spite of the significant tolerogenic response that was observed in our earlier, there are two potential limitations to the targeted delivery of CTLA-4 signaling. The first is a limited accessibility to certain large target tissues second is the need necessary to link anti-CTLA-4 antibody to different tissue specific antibodies for different targets. Further, this strategy may not be effective in treating systemic autoimmune conditions. To overcome these potential limitations, we have recently designed a novel strategy by using matured dendritic cells (DCs) as APCs and manipulating the interaction at the immunological synapse through a DC bound cross-linking anti-CTLA-4 antibody to induce regulatory T cells and tolerance to a specific antigen presented by DCs. The major advantages of this system are 1) one BiAb can be used to induce tolerance to any number of antigens; 2) it can be used to tolerize T cells against autoantigens of systemic as well as organ specific autoimmune diseases and also can induce tolerance to allergens, allo- and xeno-antigens, etc; 3) in vivo injected DCs could migrate into lymphoid structures and target organs throughout the body and inactivate antigen specific T cells; 4) use of the exceptional antigen presenting capability of DCs that could induce a much stronger regulatory T cell expansion and tolerance. Here, we propose to determine the therapeutic potential of an anti-CTLA-4 antibody coated dendritic cells and in inducing regulatory T cells. In aim-l, we will test the efficacy of BiAb in inducing regulatory T cells in vivo and in vitro. In aim-2, we will test the ability of these regulatory T cells in down modulating EAT and CIA.