Acid Sphingomyelinase Inhibition protects against experimental Multiple Sclerosis: mechanisms and translation to therapy

• Antragsteller: Professor Dr. Klaus Fassbender
• Fachliche Zuordnung: Anatomie und Physiologie
• Förderung: Förderung von 2007 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 39134126

Multiple Sclerosis (MS) is a chronic demyelinating neuroinflammatory disease, mainly affecting young adults. Immigration of leukocytes into the central nervous system (CNS) is a main pathophysiological step in this disease and is based on mutual recognition of adhesion molecules. Our data show that mice deficient for acid sphingomyelinase (Asm) are completely resistant against development of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. These findings could be reproduced by a functional blockade of Asm by the known anti-depressant amitriptyline. Asm deficiency protected against typical intraparenchymal inflammatory infiltrates. As possible mechanism, we deteced a significantly reduced adhesion of T cells to brain endothelial cells of Asm deficient or amitriptyline-treated T cells upon induction of EAE. These results may explain the observed protection of Asm blockade against EAE. In the present proposal, we further dissect (I) the cellular target of ASM in EAE (T versus endothelial cells), (II) the role of the Asm in leukocyte-endothelial interactions, (III) the specificity of our results for EAE by comparison with an other neurological autoimmune disease model and (IV) the translation to clinic by a pilot clinical trial on the effects of ASM inhibition in MS patients.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1267: Sphingolipids - Signal and Disease
• Beteiligte Person: Dr. Silke Walter