T CELL GENE EXPRESSION AND TRAFFICING IN EAE

这位候选人加入了免疫学系，并 在默克公司工作了六年后，于1986年在韦恩州立大学攻读微生物学 韦恩州立大学在神经免疫学方面尤其强大 研究。这位候选人很快抓住了这个机会，自那以后 开发了一个旨在分析T细胞受体基因的研究程序 脑源性细胞在脑内的表达和体内转运 小鼠实验性自身免疫性脑脊髓炎模型。的一部分 这项人口贩运研究目前由美国国立卫生研究院资助。T细胞的研究 受体异质性目前的部分资金来自 国家多发性硬化症协会。此外，一个重叠的 美国国立卫生研究院正在对申请进行审查。当前的目标是 研究计划是使用T细胞表面抗原作为遗传标记来 追踪脑源性细胞在体内的运输导致 EAE的发展。具体地说，髓鞘碱性蛋白(MBP)特异的 供体Thy-1.2供体T细胞将被注射到幼稚的Thy-1.1中 收件人。供体细胞在中枢神经系统和淋巴组织中的去向 接受者将被THY-1标记跟随，该标记可以是 用抗Thy-1.2的单抗检测。这种方法是 对于研究效应细胞的机制尤其重要。 处于疾病的自发复发阶段。稳定的遗传 与放射性同位素标记的细胞不同，标记可以在很长一段时间内被追踪 时间的流逝。最近，这位候选人的实验室发现 细胞转移接受者的额外抗原挑战可能导致 许多被认为具有“抗药性”品系的小鼠的疾病发展 C57BI/6和BALB/C。该实验系统为 研究EAE易感性的遗传基础。一 方法是通过以下方法检查T细胞受体(TCR)基因的使用 来自这两个菌株的脑源性细胞。有限的概念 TCR基因使用的异质性增加了人们的希望，可能是对TCR基因的调控 自身免疫性疾病可以通过操纵TCR本身来实现。 在其他小鼠身上确认这些发现是非常重要的 PL和B10.PL以外的菌株，特别是在正常情况下 抗病的抗病诱变的最终，这种对疾病的认识 将利用抗药性来设计针对人类的治疗方法 脱髓鞘疾病。这项研究计划既具有挑战性，又具有挑战性 值得一试。授予RCDA将使候选人能够获得更多 积极追求计划的目标，并促进更紧密的 与国内外神经免疫学专家的互动 部门。如申请表中所示，应聘者拥有完整的 得到部门和学校的支持。

This candidate joined the faculty of Department of Immunology and Microbiology at Wayne State University in 1986 after six years at Merck & Co. Wayne State University is particularly strong in Neuroimmunology research. The candidate quickly seized the opportunity and had since developed a research program aiming at analyzing the T cell receptor gene expression as well as in vivo trafficking of encephalitogenic cells in the murine experimental autoimmune encephalomyelitis (EAE) model. A part of the trafficking study is currently funded by NIH. The study on T cell receptor heterogeneity is currently partly funded by a grant from the National Multiple Sclerosis Society. In addition, an overlapping application is under review at NIH. The immediate objective of the research program is to use a T cell surface antigen as a genetic marker to follow the in vivo trafficking of encephalitogenic cells leading to the development of EAE. Specifically, myelin basic protein (MBP)-specific donor Thy-1.2+ donor T cells will be injected into naive Thy-1.1+ recipients. The fate of the donor cells in the CNS and lymphoid tissues of the recipients will be followed by virtue of the Thy-1 marker which can be detected with monoclonal anti-Thy-1.2 antibodies. This approach is especially important for the investigation of the effector cell mechanisms in the spontaneously relapsing phase of the disease. The stable genetic marker, unlike radioisotope-labeled cells, can be traced over a long period of time. Recently, the candidate's laboratory made the discovery that additional antigenic challenge of cell transfer recipients can lead to disease development in many reputed 'resistant' strains of mice such as C57BI/6 and BALB/C. This experimental system opens up new avenues for studying the genetic basis of susceptibility to EAE induction. One approach is to examine the T cell receptor (TCR) gene usage by encephalitogenic cells from these two strains. The concept of limited heterogeneity in TCR gene usage has raised hope that perhaps modulation of autoimmune diseases can be achieved through manipulation of the TCR itself. It will be very important to confirm these findings in additional mouse strains other than PL and B10.PL, especially in mice that are normally resistant to disease induction. Eventually, this knowledge of disease resistance will be utilized to design therapeutic approaches to human demyelinating diseases. This research program is both challenging and rewarding. The award of a RCDA will enable the candidate to more aggressively pursue the objectives of the program and to foster closer interactions with neuroimmunology experts within and outside of the Department. As noted in the application, the candidate has the full support of the Department and the School.