Mechanisms of EAE Resistance and Development of Chronic Relapsing Disease

描述(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，类似于人类多发性硬化症(MS)的临床和病理特征。在这两种情况下，都有明显的调控机制，因为个人可能对这种疾病敏感或耐药。此外，从最初的发作中恢复的个人可能成为随后自发的缓解/复发周期的受害者。该实验室的长期目标是了解EAE抵抗和病情缓解/复发的潜在机制。最近，调节性T细胞(Treg)被证明能抑制免疫效应细胞的激活。特别相关的是，发现耗尽自然Treg细胞(NTreg)会使小鼠容易受到EAE的诱导。我们发现，这种抵抗力的丧失发生在一种品系的小鼠(SJL.B)中，而在另一种品系的小鼠(B6)中则没有。具体目标1将调查这种Treg机制是否普遍被耐EAE的小鼠品系用来维持对疾病诱导的抵抗力。还提出了一个假设，解释了B6小鼠对抗CD25治疗不敏感的原因。特定目的2探索抗原诱导的Treg细胞(Treg)可能具有与nTreg细胞不同的特性。通过使用本实验室培育的Thy-1同源小鼠品系，将跟踪Treg细胞从淋巴组织到中枢神经系统的运输模式。令人特别感兴趣的是Treg细胞最有效地抑制脑源性效应细胞以预防疾病的组织位置。在此，我们将以Thy-1同源小鼠为研究对象，从表位扩散、Treg细胞和急性致病T细胞的作用等方面探讨EAE缓解/复发的机制。总而言之，这个项目将提供一个更好的了解调节性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.