MIGRATION OF PIONEER T LYMPHOCYTES INTO THE BRAIN

虽然血脑屏障被认为是经典的阻止免疫细胞进入大脑在正常条件下，从这个实验室和其他人最近的工作表明，激活的淋巴细胞，特别是CD 4 Th 1细胞，可以进入大脑在没有炎症病灶。 这种迁移途径不仅在非淋巴器官的正常免疫监视中很重要，而且在组织特异性自身免疫性疾病的起始中也很重要。 然而，调节这种淋巴细胞进入大脑的早期“浮躁”的分子介质仍然不清楚。 另一个未回答的问题是免疫监视是否是组织特异性的，或者在所有非淋巴组织中需要相同的分子步骤。 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节的，这些分子事件与炎症发生后所使用的分子事件不同。 初步工作，使用体内检测系统支持这一假设，并表明，早期迁移发生的淋巴细胞整合素非常晚抗原4（VLA-4）和内皮血管细胞粘附分子（VCAM）的独立，但需要增加内皮P选择素的表面表达。 该项目的具体目标是：首先确定已知粘附分子在Th 1细胞早期迁移到大脑中的作用，与另一个免疫特权器官胰腺相比;其次将Th 1细胞的迁移与Th 2和CD 8淋巴细胞所需的步骤进行比较;第三更详细地检查P选择素的作用及其在早期迁移细胞中的调节;第四，确定早期迁移性Th 1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。 这项工作将提供更好的了解体内免疫细胞迁移，并可能建议新的治疗策略，如多发性硬化症的中枢神经系统炎症性疾病。

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.