Grant: Operating Grant

Immune cells, called leukocytes travel from the blood to local sites of inflammation where they initiate and maintain tissue-specific immune responses. Normally, the brain is not easily accessible to cells of the immune system due to the presence of the endothelial blood-brain barrier (BBB). However, in the disease Multiple Sclerosis (MS), an autoimmune disorder of the central nervous system (CNS), a large number of inflammatory immune cells known as pro-inflammatory lymphocytes readily cross the BBB to infiltrate the brain and to trigger the formation of lesions. The movement of such aggressive lymphocytes, from the blood to the CNS, is orchestrated by many factors, including cell adhesion molecules (CAMs). CAMs enable immune cells to adhere and cross over the BBB to infiltrate the CNS. We have identified MCAM (for Melanoma Cell Adhesion Molecule) as a novel CAM expressed by endothelial cells of the BBB, and found it to play a central role in the migration of aggressive immune cells into the CNS. The current research application focuses on this newly discovered molecule used by immune cells to enter the CNS and to promote the development of MS lesions, and more specifically on the role of MCAM on the trans-migration of very aggressive and CNS-attacking CD8 lymphocytes. Using a combination of human in vitro and in situ experiments, combined with mouse in vivo models of MS, we propose to elucidate the role of MCAM in CD8 lymphocyte migration and to identify novel biological therapeutics (Antibodies that can be used in human) to neutralize MCAM and to reduce the formation of inflammatory plaques in MS. This project expands our research program which aims at identifying attractive target for the development of novel therapies for the treatment of MS and other inflammatory diseases.