LYMPHOCYTES THAT SUPPRESS EAE

描述（改编自研究者摘要）：监管（抑制） 淋巴细胞被认为在许多现象中起关键作用， 自身免疫到移植耐受。 然而，其机制 由于系统的复杂性， 研究了 为了简化问题，调查人员已经产生了一个最小的 实验性自身免疫性脑脊髓炎（EAE）小鼠模型， 多发性硬化 他们已经产生了转基因小鼠（T/R+）， 编码T细胞受体的α和β链的基因， 脑脊髓炎性T细胞克隆。 大多数T/R+小鼠没有 发展EAE。 相反，当T/R+小鼠与RAG-1 KO小鼠杂交时， 产生T/R-小鼠，100%的T/R-后代发展EAE 自发的 因为RAG-1突变阻止了T/R-小鼠 产生成熟的B和T淋巴细胞，这些小鼠唯一的淋巴细胞 含有抗MBP转基因T细胞。 相比之下，T/R+还具有 与大致相似数量的抗MBP T细胞，一些非转基因T细胞， （内源性）α/β T细胞与不同的剧目，以及 γ/δ T细胞和B细胞。 因此，T/R-小鼠构成单克隆抗体。 可以向其添加定义的蜂窝组件的系统及其 评估EAE法规的重要性。 调查人员的目标是 准确地理解这种调节是如何在细胞中发生的， 分子水平。 他们想确定淋巴细胞亚群 通过将T/R+小鼠与基因敲除小鼠杂交， 只有一个淋巴隔室缺乏T/R-小鼠，并通过注射 将纯化的（分选的）细胞亚群在免疫前和免疫后植入T/R小鼠中。 EAE发作。 此外，他们知道T/R+小鼠的EAE抗性 是由MBP特异性胸腺阳性选择失败引起的， T细胞，也没有增加这些相同细胞的阴性选择。 此外，两种组织的外周淋巴器官中的抗MBP T细胞均为阴性。 类型的小鼠不是无反应性的。 为了更好地定义 在抗MBP T细胞的调节细胞，他们也将比较抗MBP 在T细胞分化后期，T/R-小鼠的T细胞与T/R+小鼠的T细胞相比， 反应，即在“关闭”期间，通过激活诱导细胞死亡或其他 抗炎机制。 最后，有证据表明， EAE对照中的细胞也通过过继转移的EAE诱导提供 抗MBP CD 4 + Th 2细胞。 将MBP特异性Th 2细胞转移到RAG-1中 KO或TCR α KO小鼠导致EAE发展;然而，正常和 TCR δ KO小鼠受体具有抗性。 这有力地表明， α/β细胞的存在保护接受者免受EAE。 的 研究人员计划确定这些细胞的调节要求 关于特定的细胞类型，所需的最小细胞数量 以及这些细胞的特异性。 具体目标是： 1)为了鉴定TCR+/RAG+小鼠中的“保护性”T细胞亚群， 确定正在进行的炎症反应的“抑制”是否 在RAG-小鼠中改变，和3）为了定义T细胞群， 保护小鼠在转移Th 2细胞后免于发生EAE。 的 增加了对负调控的理解， 所定义的系统不仅潜在地适用于MS，而且还适用于其它系统。 自身免疫性疾病和一般耐受性的知识。

DESCRIPTION (Adapted from Investigator's abstract): Regulatory (suppressor) lymphocytes are assumed to play a key role in a number of phenomena, from autoimmunity to transplantation tolerance. However, their mechanism of action remains largely unknown due to the complex nature of the systems studied. To simplify matters, the investigators have generated a minimal mouse model of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. They have generated transgenic mice (T/R+) for the genes encoding the alpha and beta chains of the T-cell receptor from an encephalomyelitogenic T-cell clone. The majority of the T/R+ mice do not develop EAE. In contrast, when T/R+ mice were crossed with RAG-1 KO mice to generate T/R- mice, 100 percent of the T/R- progeny develop EAE spontaneously. Because the RAG-1 mutation prevents T/R- mice from generating mature B and T lymphocytes, the only lymphocytes these mice contain are anti-MBP transgenic T-cells. In contrast T/R+ have, in addition to roughly similar numbers of anti-MBP T-cells, some non transgenic (endogenous) alpha/beta T-cells with diverse repertoires, as well as gamma/delta T-cells and B-cells. Thus, T/R- mice constitute a monoclonal system to which defined cellular components can be added and their importance in EAE regulation assessed. The investigators' goal is to understand precisely how this regulation occurs at the cellular and molecular levels. They would like to identify the lymphocyte subpopulation responsible for EAE resistance by crossing T/R+ mice with mice knockout for only one of the lymphoid compartments lacking in T/R- mice, and by injecting purified (sorted) cell subpopulations into T/R- mice before and after the onset of EAE. In addition, they know that the EAE resistance of T/R+ mice is caused by neither a failure in thymic positive selection of MBP specific T-cells, nor an increased negative selection of these same cells. Furthermore, anti-MBP T-cells in the peripheral lymphoid organs of both types of mice are not anergic. In order to better define the action of regulatory cells on anti-MBP T-cells, they will also compare the anti-MBP cells of T/R- mice to those of T/R+ mice in the later stages of T-cell response, ie during "shut off", by activation induced cell death or other anti-inflammatory mechanisms. Finally, evidence for a role of regulatory cells in EAE control is also provided by EAE induction by adoptive transfer of anti-MBP CD4+ Th2 cells. Transfer of MBP specific Th2 cells into RAG-1 KO or TCR alpha KO mice results in EAE development; however, both normal and TCR delta KO mouse recipients are resistant. This strongly suggests that the presence of alpha/beta cells protects recipients against EAE. The investigators plan to define the requirements of these cells for regulation with regard to the specific cell type, the minimum number of cells necessary for regulation, and the specificity of such cells. The specific aims are: 1) To identify the "protective" T-cell subset in TCR+/RAG+ mice, 2) To determine whether the "suppression" of an ongoing inflammatory response is altered in RAG- mice, and 3) To define the population of T-cells that protects mice from developing EAE after transfer of Th2 cells. The increased understanding of negative regulation and control provided by this defined system is potentially applicable not only to MS, but also to other autoimmune diseases and to the knowledge of tolerance in general.