Migration of Pioneer T Lymphocytes into the Brain

描述（由申请人提供）：在该奖项的前两年，研究表明P选择素（CD 62 P）介导先驱T淋巴细胞迁移到中枢神经系统（CNS）。这些细胞被称为先锋细胞，因为它们可以在炎症发生之前进入大脑，它们的功能是执行免疫监视或启动炎症。有趣的是，CD 62由脑膜血管、软脑膜蛛网膜和脉络丛上皮表达，但不由实质血管表达。这些结果表明，正常的免疫监视的大脑主要是针对脑膜-脑脊液空间，而不是实质血管周围区域。为了研究CD 62 P依赖性T淋巴细胞迁移在自身免疫性疾病中的作用，本提案提出的新目标是开发一种小鼠实验性自身免疫性脑脊髓炎（EAE）的过继转移模型，该模型不需要任何操作，如辐射或佐剂，可以急性改变CD 62 P的表达。初步数据表明，（B10.PLxC57BL6/J）Fl小鼠在没有宿主免疫系统的任何先前激活或损害的情况下发展严重的过继转移EAE。对照B10.PL或（B10.PLxSJUJ）Fl小鼠要么出现轻度疾病，要么尽管存在脑膜炎症浸润，但根本没有临床损害。基于这些结果，假设T淋巴细胞正常归巢到脑膜隔室可以保护宿主免于发展严重形式的脑自身免疫性疾病，如多发性硬化症。本提案旨在进一步表征（B10.PLxC57BL6/J）F1、（B10. PLxSJUJ）F1和B10.PL小鼠，通过经典遗传学方法分析这种疾病表型的遗传复杂性，并通过使用敲除小鼠确定CD 62 P在这些疾病表型中可能具有的作用。最初的目标是确定在（B10.PLxC57BL6/J）F1小鼠中形成严重疾病表型的关键时间。长期目标是确定允许大脑正常免疫监视但抑制自身免疫性疾病发生的方法。

DESCRIPTION (provided by applicant): During the first two years of this award, it was demonstrated that P selectin (CD62P) mediates migration of pioneer T lymphocytes into the central nervous system (CNS). These cells are called pioneer cells because they can enter the brain prior to the development of inflammation, and their function is to perform immune surveillance or to initiate inflammation. Interestingly, CD62 is expressed by meningeal vessels, pia-arachnoid, and choroid plexus epithelium, but not by parenchymal vessels. These findings suggested that normal immune surveillance of the brain is primarily directed to the meningeal-cerebrospinal fluid space as opposed to parenchymal perivascular regions. In order to study the role that CD62P-dependent T lymphocyte migration plays in autoimmune disease, the new goal addressed by this proposal is to develop an adoptive transfer model of mouse experimental autoimmune encephalomyelitis (EAE) that does not require any manipulations such as irradiation or adjuvants that can acutely alter expression of CD62P. Preliminary data demonstrate that (B10.PLxC57BL6/J) Fl mice develop severe adoptive transfer EAE without any prior activation or compromise of the host's immune system. Control B10.PL or (B10.PLxSJUJ)Fl mice either develop mild disease or have no clinical impairment at all despite the presence of meningeal inflammatory infiltrates. Based on these results, it is hypothesized that normal homing of T lymphocytes to the meningeal compartment may protect the host from developing severe forms of brain autoimmune diseases such as multiple sclerosis. The aims of this proposal are to further characterize the early inflammatory pathology in (B10.PLxC57BL6/J)F1, (B10. PLxSJUJ) Fl, and B10.PL mice, analyze the genetic complexity of this disease phenotype by classical genetic methods, and to determine the role that CD62P may have in these disease phenotypes by using knockout mice. The initial goal is to determine the critical time at which commitment to a severe disease phenotype is made in (B10.PLxC57BL6/J)Fl mice. The long-term goal is to identify methods that permit normal immune surveillance of the brain but inhibit the initiation of autoimmune disease.