Contributions
Abstract: P435
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Introduction: The blood-brain barrier (BBB) strictly controls lymphocyte entry into the central nervous system (CNS). The BBB breakdown, with a subsequent infiltration of inflammatory cells into the CNS, is an early key step in the pathogenesis of multiple sclerosis (MS). Although recent MS drugs targeting immune cell trafficking (e.g. Natalizumab and fingolimod) are highly effective, these treatments are associated with rare but severe side effects like progressive multifocal leukoencephalopathy (PML), suggesting that the current therapies also target immune cells mediating immunosurveillance of the CNS. It is thus essential to differentiate disease relevant pathogenic T cell subsets from non-pathogenic subsets and to explore differences in the molecular mechanisms for entering the CNS. To this end molecular mechanisms has largely been studied in experimental autoimmune encephalomyelitis (EAE), but EAE does not mimic the full picture of MS neuropathology. This underscores the need of meaningful studies with human tissues and cells. We have recently established a novel in vitrohuman BBB model by co-culturing human CD34+cord blood cells derived endothelial cells with bovine pericytes. Here we have adapted this model for use in T-cell migration research.
Objective and Aims: To study if human CD4+effector T cells cross the BBB through the endothelial junction (paracellular) or through a pore in the endothelial cells (transcellular) we have started to investigate the role of the junctional adhesion molecules PECAM-1 and CD99 in this process. PECAM-1 and CD99 have been shown mediate diapedesis of neutrophils across peripheral vascular beds. Their role in mediating the migration of CD4+T cell subsets across the BBB remains to be explored.
Methods and Results: Applying blocking antibodies, we observed anti-CD99 blocking antibodies reduce CD4+T cell migration across the BBB in vitro, while anti-PECAM-1 blocking antibodies did not interfere with this process.
Conclusions: These data shows that human effector CD4+T cell have different molecular mechanisms employed for crossing the BBB compare to innate immune cells.
Disclosure: Hideaki Nishihara was supported by ECTRIMS Postdoctoral Research Fellowship Exchange Programme and Uehara memorial foundation.
This study was funded by the Swiss National Science Foundation (CRSII3_154483, Sinergia UnmetMS) to Britta Engelhardt and Federica Sallusto, the Swiss Multiple Sclerosis Society to Adrien Mossu, the Germaine de Stael PHC program to Fabien Gosselet and Britta Engelhardt,the Gottfried und Julia Bangerter-Rhyner-Stiftung supported this study to Britta Engelhardt.
William A Muller: nothing to disclose.
Abstract: P435
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Introduction: The blood-brain barrier (BBB) strictly controls lymphocyte entry into the central nervous system (CNS). The BBB breakdown, with a subsequent infiltration of inflammatory cells into the CNS, is an early key step in the pathogenesis of multiple sclerosis (MS). Although recent MS drugs targeting immune cell trafficking (e.g. Natalizumab and fingolimod) are highly effective, these treatments are associated with rare but severe side effects like progressive multifocal leukoencephalopathy (PML), suggesting that the current therapies also target immune cells mediating immunosurveillance of the CNS. It is thus essential to differentiate disease relevant pathogenic T cell subsets from non-pathogenic subsets and to explore differences in the molecular mechanisms for entering the CNS. To this end molecular mechanisms has largely been studied in experimental autoimmune encephalomyelitis (EAE), but EAE does not mimic the full picture of MS neuropathology. This underscores the need of meaningful studies with human tissues and cells. We have recently established a novel in vitrohuman BBB model by co-culturing human CD34+cord blood cells derived endothelial cells with bovine pericytes. Here we have adapted this model for use in T-cell migration research.
Objective and Aims: To study if human CD4+effector T cells cross the BBB through the endothelial junction (paracellular) or through a pore in the endothelial cells (transcellular) we have started to investigate the role of the junctional adhesion molecules PECAM-1 and CD99 in this process. PECAM-1 and CD99 have been shown mediate diapedesis of neutrophils across peripheral vascular beds. Their role in mediating the migration of CD4+T cell subsets across the BBB remains to be explored.
Methods and Results: Applying blocking antibodies, we observed anti-CD99 blocking antibodies reduce CD4+T cell migration across the BBB in vitro, while anti-PECAM-1 blocking antibodies did not interfere with this process.
Conclusions: These data shows that human effector CD4+T cell have different molecular mechanisms employed for crossing the BBB compare to innate immune cells.
Disclosure: Hideaki Nishihara was supported by ECTRIMS Postdoctoral Research Fellowship Exchange Programme and Uehara memorial foundation.
This study was funded by the Swiss National Science Foundation (CRSII3_154483, Sinergia UnmetMS) to Britta Engelhardt and Federica Sallusto, the Swiss Multiple Sclerosis Society to Adrien Mossu, the Germaine de Stael PHC program to Fabien Gosselet and Britta Engelhardt,the Gottfried und Julia Bangerter-Rhyner-Stiftung supported this study to Britta Engelhardt.
William A Muller: nothing to disclose.