Migration of Pioneer T Lymphocytes into the Brain

描述(由申请人提供)：在该奖项的头两年，P选择素(CD62P)被证明介导先锋T淋巴细胞向中枢神经系统(CNS)的迁移。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，CD62在脑膜血管、软脑膜和脉络丛上皮细胞中表达，但在实质血管中不表达。这些发现表明，正常的大脑免疫监视主要针对脑膜-脑脊液间隙，而不是实质血管周围区域。为了研究CD62p依赖的T淋巴细胞迁移在自身免疫性疾病中的作用，本研究的新目标是建立一种过继转移的小鼠实验性自身免疫性脑脊髓炎(EAE)模型，该模型不需要任何操作，如照射或佐剂，可以显著改变CD62p的表达。初步数据显示，(B10.PLxC57BL6/J)F1小鼠在没有任何宿主免疫系统事先激活或损害的情况下发生严重的过继转移EAE。对照B10.PL或(B10.PLxSJUJ)F1小鼠要么发展为轻度疾病，要么完全没有临床损害，尽管存在脑膜炎性浸润物。根据这些结果，推测T淋巴细胞正常归巢到脑膜室可能会保护宿主免受严重形式的脑自身免疫性疾病的影响，如多发性硬化症。这项建议的目的是进一步描述(B10.PLxC57BL6/J)F1，(B10.用经典的遗传学方法分析这种疾病表型的遗传复杂性，并利用基因敲除小鼠来确定CD62P可能在这些疾病表型中所起的作用。最初的目标是确定(B10.PLxC57BL6/J)F1小鼠发生严重疾病表型的关键时间。长期目标是确定允许对大脑进行正常免疫监视但抑制自身免疫性疾病启动的方法。

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.