Probert, Lesley

Hellenic Pasteur Institute
Athens | Greece

Studied Biology and received her PhD in Medicine from the University of London, UK. She trained as post-doc at the Universities of London (Imperial College) and Cambridge (Laboratory of Molecular Biology), UK and in the Laboratory of Molecular Genetics at the Hellenic Pasteur Institute (HPI) in Athens, Greece. Since 2000 she has been head of the Laboratory of Molecular Genetics at the HPI.

Her main research interest is the interface between the immune system and the central nervous system (CNS), particularly the participation of the immune system in physiological brain processes such as host defense, and in inflammatory diseases such as multiple sclerosis (MS). The laboratory has a long-standing interest in understanding the functions of a pro-inflammatory cytokine, tumor necrosis factor (TNF), in the CNS. TNF drives inflammatory responses to infection, injury and neurodegeneration, but paradoxically also protects neurons, directly and indirectly by repairing the myelin sheath around demyelinated axons. This diversity of TNF function is now understood to be a direct reflection of its complex biology. “TNF” represents at least a two-ligand (soluble TNF and membrane TNF), two-receptor (TNF receptors 1 and 2/TNFR1 and TNFR2) system with ligands and receptors both differentially expressed and regulated on different cell types. Through the application of sophisticated spatial and temporal gene-targeting techniques in mice, it is possible to dissect the individual functions of the two TNFs and their receptors in a number of important brain processes through the study of experimental disease models. In general soluble TNF/TNFR1 interactions dominate inflammatory responses, which often leading to significant secondary tissue damage and also strongly inhibit remyelination. In contrast, membrane TNF/TNFR2 interactions promote remyelination and neuroprotection, by enhancing oligodendrocyte precursor cells.

The ability to separate deleterious and beneficial effects of TNF at a molecular level has direct implications for therapy in human disease. Non-selective TNF inhibitors that block the effects of both soluble and membrane TNF and are blockbuster drugs for peripheral inflammatory diseases such as rheumatoid arthritis, behave badly in the CNS. They exacerbate MS and can even induce de novo demyelinating disease. The experimental data now clearly suggest that selective inhibition of soluble TNF and/or TNFR1, while preserving membrane TNF and/or TNFR2, is a promising future direction for safe immunotherapy in chronic inflammatory diseases of the CNS like MS.

Lesley has 81 original research publications and reviews in international journals and serves as an ad hoc reviewer for numerous international journals and funding bodies. She is a member of the Board of the European School of Neuroimmunology (ESNI), Vice-President of the Hellenic Academy of Neuroimmunology (HELANI), and Secretary/Treasurer of the International Society of Neuroimmunology.