IMMUNE DEVIATION INDUCED BY GENE VACCINATION--APPLICATIONS TO ARTHRITIS

风湿性关节炎是一种慢性炎症性疾病， 外周滑膜关节类风湿关节炎的发病机制 似乎是多因素的，包括遗传易感性， 出生后免疫成熟的事件，反复暴露于环境 抗原和放大细胞因子网络，使炎症持续存在。 致病抗原可直接表达于免疫原性位点， 攻击PR可以与天然存在于 接头。我们假设，刺激一个T细胞亚群， 结合到关节特异性抗原以分泌IL 4或IL 10， 抗原呈递环境可以消除疾病。在我们的初步调查中 实验中，我们开发了一种系统， 通过注射到皮肤或肌肉组织中的质粒DNA表达， 小鼠T细胞对这些抗原的反应也是有偏向的， 不仅通过表位表达，而且通过不同的共刺激因子 在附近表达的分子。这种提供不同 参与引发免疫应答的元件产生局部免疫应答， 免疫窗在我们的实验室里，我们还开发了一种独特的 系统以限制抗原呈递至CD1同种型。我们的目标是1） 评估不同的共刺激分子对偏离 对胶原蛋白免疫应答2）确定是否提供额外的抗原 分子伴侣或共价连接抗原分子伴侣增强免疫应答， 偏离3）评价CD1D1限制性应答的调节作用 在胶原诱导的关节炎和4）确定是否形成我们的研究结果 胶原诱导的关节炎模型中的三种策略适用于 不同的转基因小鼠模型，其中小鼠自发发育 关节炎

Rheumatoid arthritis is a chronic inflammatory disease primary affecting peripheral synovial joints. The etiopathogenesis of rheumatoid arthritis appears to be multi-factorial, including hereditary susceptibility, postnatal events in immune maturation, repeated exposure to environmental antigens and amplifying cytokine networks that perpetuate inflammation. The causative antigens may be directly expressed at the site of immune attack pr be cross reactive with antigenic epitopes naturally occurring in the joint. We postulate that stimulating a subset of T cells that respond to a joint specific antigen to secrete IL4 or IL10 by manipulating the antigen presenting environment may abrogate disease. In our preliminary experiments we have developed a system whereby limited epitopes are expressed by plasmid DNA injected into the dermis or muscle tissues of mice. The T cell response to these antigens is additionally biased not only by the epitope expressed, but also by different co-stimulatory molecules expressed in the vicinity. This method of providing different elements involved in priming of an immune response creates a local immunologic window. In our laboratory we have also developed a unique system to limit antigen presentation to an isoform of CD1. We aim to 1) assess the effects of different co-stimulatory molecules on deviating the immune response to collagen 2) determine if providing additional antigenic chaperones or covalently linking the antigen chaperones potentiates immune deviation 3) evaluate a regulatory role for the CD1D1 restricted responses in collagen induced arthritis and 4) determine if the findings form our three strategies in the collagen induced arthritis model apply to a different transgenic mouse model in which the mice spontaneously develop arthritis.