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.
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