IL2 DEFICIENCY MEDIATES AUTOIMMUNITY IN MRL-LPR MICE

许多诱导的自身免疫模型需要增强免疫 对特定靶组织的反应。 区别来说，自然有几个 系统性红斑狼疮（SLE）小鼠模型的出现 T 淋巴细胞反应低反应，特别是缺乏 IL2 的产生。 这在 MRL-lpr 小鼠中尤为明显。 这些 小鼠发展出 SLE 素质，并伴随着大量的积累 产生异常 TCR-alphBeta CD2- B220- B220 CD4-CD-8 T 细胞 IL2 激活后可以忽略不计，因此几乎没有表现出来 增殖能力。 它们类似于无反应性 T 细胞和其他细胞 CD2-T细胞。 lpr 缺陷是 fas 基因突变的结果 介导细胞凋亡。 这可能解释了明显的 T 细胞的积累，但不能轻易解释发育过程 这些细胞的停滞，也不是信号缺陷的原因 转导以及 IL2 的产生。 本提案将审查这一点 IL2基因调控转录因子水平的缺陷。 然后，它将评估 IL2 体内治疗在 MRL-中的潜在益处 lpr 小鼠并监测 T 细胞表型和功能的变化 这可能是造成这种情况的原因。 第一个具体目标分析IL2基因调控的表达 新鲜和培养的 MRL-lpr 中凝胶迁移率变化的转录因子 CD4-8-、CD4+ 和 MRL/T 细胞在用 PMA 和激活前后 离子霉素或抗 CD3 单克隆抗体。 这将与刺激的 T 细胞进行比较 在不存在或存在抗 fas mAb 的情况下使用抗 CD3 mAb。 这个 部分将定义 lpr CD4-8-T 细胞中 IL2 缺陷的性质，以及 帮助确定 fas 在 IL2 共刺激中的贡献 生产。 第二个具体目标将扩展体外初步研究 观察到 IL2 可以诱导细胞周期、CD2 诱导、B220 损失、 lpr CD4-8-T细胞获得功能。 MRL-lpr 小鼠将 将 IL2 作为 cDNA 构建体体内施用，作为表型和 CD4-9- 的功能受到监测，而潜在的有益或 确定了对自身免疫过程的有害影响。

Many induced models of autoimmunity necessitate augmenting the immune response to a specific target tissue. In distinction, several naturally arising mouse models of systemic lupus erythematosus (SLE) manifest hyporesponsive T lymphocyte responses, particularly regarding deficient IL2 production. This is strikingly present in the MRL-lpr mouse. These mice develop an SLE diathesis accompanied by an enormous accumulation of abnormal TCR-alphBeta+ CD2- B220- B220+ CD4-CD-8 T cells that produce negligible IL2 when activated and as a result, manifest little proliferative capacity. A such they resemble anergic T cells and other CD2-T cells. The lpr defect results form a mutation of the fas gene which mediates apoptosis. This may account for the pronounced accumulation of T cells, but does not readily explain the developmental arrest of these cells, nor the reason for the defect in signal transduction and hence IL2 production. This proposal will examine this defect at the level of the IL2 gene regulatory transcription factors. It will then assess the potential benefits of IL2 in vivo therapy in MRL- lpr mice and monitor the alterations in T cell phenotype and function that may be responsible for this. The first specific aim analyzes the expression of the IL2 gene regulatory transcription factors by gel mobility shift in fresh and cultured MRL-lpr CD4-8-, CD4+, and MRL+/+ T cells before and after activation with PMA and ionomycin, or anti-CD3 mAb. This will be compared to T cells stimulated with anti-CD3 mAb in the absence or presence of anti-fas mAb. This portion will define the nature of the IL2 defect in lpr CD4-8-T cells and help establish the contribution if fas in costimulation of IL2 production. The second specific aim will extend the preliminary in vitro observation that IL2 can induce cell cycling, CD2 induction, B220 loss, and gain of function by lpr CD4-8- T cells. MRL-lpr mice will be administered IL2 in vivo as a cDNA construct, as the phenotype and function of the CD4-9- monitored while the potential beneficial or detrimental effects on the autoimmune process are determined.