Immunopathogenesis of Lupus

描述(申请人提供)：长期目标是开发一种治疗人类狼疮的新疗法，这种疗法比目前可用的免疫抑制疗法副作用更少，并具有更高的疗效。为此，我们使用了狼疮的临床前模型，并证明了免疫调节，即偏离抗体产生的免疫反应，并增强细胞介导的免疫以包括细胞毒性T淋巴细胞在该模型中既可行又有益。目前的建议还表明，狼疮易感性可能与白介素2的预先存在的缺陷有关，白介素2促进免疫偏斜。利用体内和体外方法并结合流式细胞术、遗传学和细胞免疫学，这项建议有以下目标：1)利用临床前模型确定IL-2的缺陷T细胞产生是否会导致狼疮，及其发生的机制，IL-2替代是否有益，并采用小鼠的方法来筛选类似异常的人类狼疮患者；2)开发非基于IL-2的免疫调节方法(如TLR激动剂)，并在几种小鼠模型中测试其有效性；3)在小鼠模型中确定调节狼疮严重程度性别差异的机制(S)。这些研究将为IL-2在狼疮发病机制中的作用提供新的见解，并确定新的非免疫抑制治疗狼疮的方法。

DESCRIPTION (provided by applicant): The long term objectives are to develop a novel treatment for human lupus that has fewer side effects than currently available immunosuppressive treatment and has improved efficacy. To this end, we have used a pre-clinical model of lupus and demonstrated that immunomodulation, i.e. skewing of the immune response away from antibody production and enhancing cell mediated immunity to include cytotoxic T lymphocytes is both feasible and beneficial in this model. The current proposal also demonstrates that lupus predisposition may relate to a pre-existing defect in interleukin-2 which promotes immune skewing. Using in vivo and vitro approaches combined with flow cytometry, genetic analysis and cellular immunology, this proposal has the following aims: 1) use pre-clinical models to determine whether defective T cell production of IL-2 predisposes to lupus, the mechanism by which this occurs, whether IL-2 replacement will be beneficial and adapt the murine approach to screen human lupus patients for similar abnormalities; 2) develop non IL-2 based immunomodulatory approaches (e.g., TLR stimulants) and test their efficacy in several murine models; 3) define the mechanism(s) that mediate sex differences in lupus severity in a murine model. These studies will provide novel insights into the role of IL-2 in lupus pathogenesis and identify new, non-immunosuppressive therapeutic approaches to lupus treatment.