RESISTANCE MECHANISMS-- MURINE ADOPTIVE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

关于易感人群致病机制的研究 动物往往能洞察疾病是如何产生的。同样， 关于如何在耐药菌株中预防疾病的研究也可以提供 了解疾病过程的信息。的目标是 这项提议是使用遗传和免疫化学方法来探测 对诱导产生抵抗力的一些因素 实验性自身免疫性脑脊髓炎(EAE)。通过收养 在易感(SJL)和易感(SJL)之间转移脑源性细胞 耐药(B10.S)小鼠品系的抗原性和抗原性 脑内皮细胞在疾病抵抗力中的评估(特定目的 1)。这些实验得到了Thy-1同源基因的新用途的帮助 允许快速鉴定供体和宿主T细胞的菌株 中枢神经系统组织切片。在具体目标2中，是否 脑血管内皮细胞上MHC抗原的表达 研究了脑源性细胞进入中枢神经系统的途径。这是 通过从一个易感人群中转移脑源性细胞实现的 供体(SJL)移植到另一个同种异体易感宿主(PL)。自.以来 宿主内皮细胞表达MHC抗原(如果有的话)将不会 与捐赠者的T细胞相匹配，任何疾病的发展都将 提示血管内皮细胞对MHC抗原的识别 生脑细胞不是必需的。在具体目标3中，新鲜 脑血管内皮细胞是在体外建立的，同样 在特定目标1和2中的淋巴细胞-内皮细胞组合是 用来检查淋巴细胞通过单层的 内皮细胞。结果将与体内的 观察。在特定的目标4中，宿主T细胞在 两步传输挑战协议中的EAE生成为 调查过了。该方案成功地诱导了EAE抗性 这些实验的菌株和结果将为我们提供关于 这些小鼠对EAE的抵抗力被克服。最后，在具体目标5中， 将使用生化技术绘制髓鞘碱性蛋白T的图谱 转染法刺激耐药B10.S小鼠的细胞表位 质询协议。这些表位将与公认的表位进行比较 通过敏感的SJL细胞，因为两个菌株共享相同的MHC 单倍型。本项目取得的成果，以及 从项目1开始，应全面了解 耐药机制，尤其是淋巴细胞与细胞间的相互作用 脑内皮细胞在EAE发生发展中的作用。此信息 将有助于设计治疗方法来治疗这种自身免疫疾病 疾病。

Studies investigating the mechanisms of disease induction in susceptible animals often provide insight into how disease is initiated. Similarly, studies on how disease is prevented in resistant strains can also provide information for understanding the disease processes. The objective of this proposal is to use genetic and immunochemical approaches to probe some of the factors that confer resistance to the induction of experimental autoimmune encephalomyelitis (EAE) in mice. By adoptively transferring encephalitogenic cells between susceptible (SJL) and resistant (B10.S) mouse strains, the roles of antigen priming and of the cerebral endothelium in disease resistance are evaluated (specific aim 1). These experiments are aided by the novel use of Thy-1 congenic strains that allows rapid identification of donor versus host T cells in sections of CNS tissues. In specific aim 2, the question of whether expression of MHC antigens on cerebral endothelium is required for passage of encephalitogenic cells into the CNS is investigated. This is achieved by transferring encephalitogenic cells from one susceptible donor (SJL) into another allogeneic susceptible host (PL). Since expression of MHC antigens, if any, by the host endothelium will not be compatible with the donor T cells, any development of disease will indicate that recognition of MHC antigens on endothelial cells by encephalitogenic cells is not essential. In specific aim 3, fresh cerebral endothelial cells are established in vitro and the same lymphocyte-endothelial cell combinations as in specific aims 1 and 2 are used to examine the passage of lymphocytes through monolayers of endothelial cells. Results will be correlated with the in vivo observations. In specific aim 4, the role of host T cells in the generation of EAE in the two-step transfer-challenge protocol is investigated. This protocol successfully induces EAE in resistant strains and results from these experiments will provide insights into how EAE resistance in these mice is overcome. Finally, in specific aim 5, biochemical techniques will be used to map the myelin basic protein T cell epitopes stimulatory to the resistant B10.S mice using the transfer- challenge protocol. These epitopes will be compared to those recognized by the susceptible SJL cells as both strains share the same MHC haplotypes. The results obtained in this project, together with those from Project 1, should provide a comprehensive understanding of the resistant mechanism, especially the interactions between lymphocytes and the cerebral endothelium, in the development of EAE. This information will aid the design of therapeutic approaches to treat this autoimmune disease.