MIGRATION OF PIONEER T LYMPHOCYTES INTO THE BRAIN

尽管血脑屏障被经典地认为是在正常情况下阻止免疫细胞进入大脑，但该实验室和其他实验室最近的研究表明，在没有炎症灶的情况下，激活的淋巴细胞，特别是CD4Th1细胞可以进入大脑。这种迁移途径不仅在非淋巴器官的正常免疫监测中很重要，而且在组织特异性自身免疫病的发生中也很重要。然而，调节淋巴细胞进入大脑的这种早期“浮躁”的分子介体仍不清楚。另一个悬而未决的问题是，免疫监测是组织特异性的，还是需要在所有非淋巴组织中采取相同的分子步骤。我们假设，这些“先锋”淋巴细胞进入大脑是由一系列分子事件调控的，这些分子事件不同于一旦炎症建立后使用的那些事件。使用体内检测系统的初步工作支持这一假说，并证明早期迁移发生不依赖于淋巴细胞整合素甚晚期抗原4(VLA-4)和内皮血管细胞黏附分子(VCAM)，但确实需要增加内皮P选择素的表面表达。该项目的具体目的是：第一，确定已知的黏附分子在Th1细胞早期迁移到大脑中的作用，与另一免疫豁免器官胰腺相比；第二，比较Th1细胞的迁移与Th2和CD8淋巴细胞所需的步骤；第三，更详细地研究P选择素的作用以及早期迁移细胞对P选择素的调节；第四，确定早期迁移Th1细胞对自身免疫性疾病小鼠模型-实验性自身免疫性脑炎(EAE)的调节作用。这项工作将提供对体内免疫细胞迁移的更好理解，并可能为多发性硬化症等中枢神经系统炎症性疾病提供新的治疗策略。

Although the blood brain barrier was thought classically to block the entry of immune cells into the brain under normal conditions, more recent work from this laboratory and others suggests that activated lymphocytes, particularly CD4 Th1 cells, can enter the brain in the absence of an inflammatory focus. This migratory pathway is important not only in normal immune surveillance of non-lymphoid organs but also in the initiation of tissue-specific autoimmune disease. However, the molecular mediators that regulate this early "blundering" of lymphocytes into the brain remain unclear. An additional unanswered question is whether immune surveillance is tissue specific or requires the same molecular steps in all non-lymphoid tissues. We hypothesize that the entry of these "pioneer" lymphocytes into the brain is regulated by a set of molecular events that are distinct from those used once inflammation has been established. Preliminary work using an in vivo assay system supports this hypothesis and demonstrates that early migration occurs independent of the lymphocyte integrin very late antigen 4 (VLA-4) and endothelial vascular cell adhesion molecule (VCAM) but does require increased surface expression of endothelial P selectin. The specific aims of this project are first to determine the role of known adhesion molecules in the early migration of Th1 cells into the brain as compared to another immune privileged organ, the pancreas; second to compare migration of Th1 cells to the steps required for Th2 and CD8 lymphocytes; third to examine in more detail the role of P selectin and its regulation by early migrating cells; and fourth to determine the modulation of a mouse model of autoimmune disease, experimental autoimmune encephalitis (EAE), by early migrating Th1 cells. This work will provide improved understanding of in vivo immune cell migration and may suggest new treatment strategies for inflammatory disorders of the central nervous system such as multiple sclerosis.