AUTOIMMUNITY AND CHRONIC LYME ARTHRITIS

自身免疫和慢性莱姆关节炎

• 批准号: 6374815
• 负责人: ABBIE L MEYER
• 金额: $ 4.38万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-23 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6374815
• 关键词: Borrelia; Lyme disease; SCID mouse; adult human (21+); autoantigens; autoimmunity; chronic disease /disorder; clinical research; cross immunity; disease /disorder model; drug resistance; flow cytometry; genetically modified animals; human subject; major histocompatibility complex; passive immunization; synovial fluid

The overall objective of this application is to confirm the identity of a possible autoantigen in antibiotic-resistant chronic Lyme arthritis. A small population of people infected with Borrelia Burgdorferi (Bb), the causative agent of Lyme disease, develop long term arthritis in one or more joints. Because: 1) The arthritis is not cured by long term use of antibiotics, 2) Many susceptible individuals are HLA-DRB10401 (DR4), and 3) T cells responding to both Bb surface antigen, Osp A and a human protein, hLFA-1, can be isolated from synovial fluid, an autoimmune etiology is suspected. Our first objective is to develop a model of chronic Lyme arthritis in mice by generating a transgenic (Tg) mouse line that expresses human. LFA-1, the suspected autoantigen as well as DR4. In these mice we will demonstrate that T cells specific for hLFA1 mediate chronic arthritis and can transfer disease to naive mice. Additionally we will generate fluorescently labeled hLFA-1332-343 and Osp A164-173 peptide-MHC tetramers that can bind and label T cells which express TCR specific for peptide. This will enable us to analyze whether the Osp A specific cell is also hLFA-1 specific, identifying a population of self-recognizing cross-reactive cells. We will transfer these human autoantigen specific cells into hLFA-1 TgDR4+/+ Beige-SCID mice and confirm their ability to generate arthritis. Data supporting an autoimmune etiology of chronic arthritis will allow physicians to begin treating this disease as an autoimmune rather than infectious disease.

该应用的总体目的是确认 抗生素耐药性慢性莱姆关节炎中可能的自身抗原。 一小部分感染Borrelia Burgdorferi（BB）的人， 莱姆病的病因，在一个中发展长期关节炎 或更多关节。因为：1）长期使用关节炎无法治愈 抗生素，2）许多易感个体是HLA-DRB10401（DR4）， 3）T细胞对BB表面抗原，OSP A和人类响应 蛋白质HLFA-1可以从滑液中分离出自身免疫性 怀疑病因。 我们的第一个目标是开发一个模型 通过产生转基因（TG）小鼠的小鼠慢性莱姆关节炎 表达人类的线。 LFA-1，可疑的自动抗原以及 DR4。 在这些小鼠中，我们将证明T细胞针对HLFA1 介导慢性关节炎，并可以将疾病转移到天真的小鼠中。 此外，我们将生成荧光标记的HLFA-1332-343和 OSP A164-173肽-MHC四聚体，可以结合和标记T细胞 表达特异性肽的特异性TCR。 这将使我们能够分析 OSP特定细胞是否也是HLFA-1特异性的，识别 自我认可的交叉反应性细胞的种群。 我们将转移 这些人类自动抗原特异性细胞中的HLFA-1 TGDR4+/+米色scid 小鼠并确认其产生关节炎的能力。 数据支持 慢性关节炎的自身免疫性病因将使医生能够 开始将这种疾病视为自身免疫，而不是传染性 疾病。