Mechanisms of EAE Resistance and Development of Chronic Relapsing Disease

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是一种中枢神经系统（CMS）自身免疫性疾病，与人类多发性硬化症（MS）的临床和病理特征相似。在这两种情况下，都有明显的调节机制，因为个体可能对疾病易感或具有抵抗力。此外，从最初发作中恢复的个体可能成为随后缓解/复发的自发周期的受害者。该实验室的长期目标是了解EAE耐药性和缓解/复发性疾病发展的机制。最近，调节性T细胞（Treg）已显示出抑制免疫效应细胞的活化。特别相关的是发现耗尽天然Treg细胞（nTreg）使小鼠对EAE诱导敏感。我们发现，这种抗性丧失发生在一种品系的小鼠（SJL.B）中，但在另一种品系的小鼠（B6）中没有。具体目标1将研究这种Treg机制是否被EAE抗性小鼠品系普遍利用以维持疾病诱导的抗性。还提出了解释B6小鼠对抗CD 25治疗不敏感的假设。具体目标2探索了抗原诱导的Treg细胞（Treg）可能具有与nTreg细胞不同的特征的可能性。通过使用本实验室开发的Thy-1同源小鼠品系，将跟踪Treg细胞从淋巴组织到CNS的运输模式。特别感兴趣的是Treg细胞最有效地抑制致脑炎效应细胞以预防疾病的组织位置。Treg细胞和缓解/复发EAE之间的可能联系在具体目标3中做出。本文以Thy-1同源小鼠为研究对象，从表位扩散、Treg细胞和急性疾病起始T细胞的作用等方面探讨EAE缓解/复发的机制。总之，该项目将更好地了解调节性T细胞如何帮助抵抗EAE和MS的发展。该项目还研究了疾病复发的机制，最终目的是设计更好的治疗方法来管理这种自身免疫性疾病。

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is a central nervous system (CMS) autoimmune disease that resembles the clinical and pathological features of human multiple sclerosis (MS). In both cases, there are clearly regulatory mechanisms as an individual can be susceptible or resistant to the disease. In addition, individuals recovering from the initial attack may fall victim to subsequent spontaneous cycles of remission/relapses relapses. This laboratory's long-term goals are to understand the mechanisms underlying EAE resistance and development remitting/relapsing disease. Recently, regulatory T cells (Treg) have been shown to inhibit the activation of immune effector cells. Of particular relevance is the finding that depleting natural Treg cells (nTreg) renders mice susceptible to EAE induction. We find that this loss of resistance occurs in one strain of mice (SJL.B) but not in another (B6). Specific aim 1 will investigate if this Treg mechanism is universally utilized by EAE resistant mouse strains to maintain resistance of disease induction. A hypothesis to account for the insensitivity of B6 mice to anti-CD25 treatment is also proposed. Specific aim 2 explores the possibility that antigen-induced Treg cells (Treg) may have differential characteristics from nTreg cells. By using Thy-1 congenic mouse strains developed in this laboratory, the trafficking patterns of Treg cells from the lymphoid tissues to the CNS will be tracked. Of particular interest is the tissue locations whereby Treg cells most efficiently inhibit encephalitogenic effector cells to prevent disease. A possible link between Treg cells and remitting/relapsing EAE is made in specific aim 3. Here, the mechanisms of remitting/relapsing EAE will be investigated from the prospects of epitope spreading, Treg cells and the roles of the acute disease-initiating T cells, using Thy-1 congenic mice. In summary, this project will provide a better understanding of how regulatory T cells help to resist development of EAE and MS. The project also studies the mechanisms of how disease relapses occurs, with the ultimate aim of designing better therapeutic approaches toward management of this autoimmune disease.