Mechanisms of Lymphocytes Transmigration Across the Blood Brain Barrier (MELTRA-BBB)

Activated T cells can enter the CNS also when there are no obvious signs of inflammation. These cells enter the CNS in order to survey this organ for bacterial or viral infection, and possibly to eliminate malignant or transformed cells. But once the CNS is the focus of an immune attack, as seen in patients of multiple sclerosis, its gates are opened so that a dramatic inflammatory process occurs. The mission of MELTRA-BBB is to investigate the early steps of CNS immune cells infiltration, and to understand what allows B and T cells to pass the blood-brain barrier (BBB) and initiate the inflammatory process. Our consortium is composed of members that have all been working for many years in the field of multiple sclerosis and its mouse model, the experimental autoimmune encephalomyelitis. Together, we gather a rare combination of expertise in mouse genetics, in the biology of endothelial cells, immunology, neuropathology and intravital imaging that makes it an ideal team to investigate the mechanisms leading to lymphocyte entry to the CNS. We will use genetic methods to delete cytokine receptors or to ablate specific cells of the immune system, and follow the development of disease in these mice. We will use cell culture systems to translate the mouse findings to the human system. We will further expand these in vivo and in vitro findings in human, by studying human MS patients lymphocytes and by characterizing these inflammatory cells in situ in MS brains. We expect that by the combination of studies in experimental models and human disease our results will have broad relevance for inflammatory diseases of the CNS as a whole and will be utilized to design better therapies for the patients of these diseases.

The project is part of an international cooperative effort (MELTRA-BBB), which includes research institutions on Germany, France, Austria, Canada and Slovakia, funded in the frame of the ERA-Net Call Neuron. The mission of MELTRA-BBB is to investigate the early steps of CNS immune cells infiltration, and to understand what allows B and T cells to pass the blood- brain barrier (BBB) and initiate the inflammatory process in experimental disease models. In addition, a major part of this project, conducted in the Center for Brain Research of the Medical University of Vienna, was devoted to the analysis of the nature of the inflammatory response in human diseases, such as multiple sclerosis, other inflammatory diseases of the nervous system and non-inflammatory diseases, such as Stroke and Alzheimers disease. In addition, this institution provided the neuropathological expertise, necessary for the interpretation of results obtained in experimental models created by the partners. This report covers the scientific achievements obtained in the Center for Brain Research. Multiple sclerosis is a chronic inflammatory disease of the central nervous system, which leads to focal demyelinated lesions and diffuse neurodegeneration in the brain. Although the inflammatory nature of the disease is known for long time, so far little information is available on the exact nature of the inflammatory process and its relation to active tissue injury. Our project shows that there are two populations of inflammatory cells, which dominate in the MS brain, the CD8+ T-lymphocytes and the B-lymphocytes. Both cell types enter the brain in fresh lesions and show signs of activation. Thus, these cells are the main candidates to trigger the inflammatory response in the central nervous system of the patients. CD8+ T-cells gradually transform into tissue resident T-cells, which persist in the brain for long time, but can become focally activated and propagate the chronic inflammatory reaction. The B- lymphocytes also enter the brain in fresh lesions, but these cells gradually transform into immunoglobulin producing plasma cells. The T-cells appear to be instrumental in the propagation of the chronic inflammatory response, while the B-cells may be involved in the induction of demyelination and tissue destruction through the production of soluble neurotoxic factors. The T-cell response in MS is similar to that seen in other, for instance virus induced inflammatory diseases of the nervous system, and the critical role of the CD8+ T-cells in the pathogenesis of brain inflammation is shown in our cooperative experimental studies, performed in collaboration with other members of this consortium. In contrast the B-cell response is much more pronounced in the brain of MS patients compared to the other diseases. These results for the first time provide a detailed account on the nature of the inflammatory reaction in the MS brain and provide valuable information for the development of new anti-inflammatory therapies for the patients.