The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage
Stig Hill Christiansen, Xianwei Zhang, Kristian Juul-Madsen, Michael Lykke Hvam, Brian Stougaard Vad, Manja Annette Behrens, Ida Lysgaard Thygesen, Babak Jalilian, Jan Skov Pedersen, Kenneth A Howard, Daniel E Otzen, Thomas Vorup-Jensen
Biochimica et Biophysica Acta (BBA) - Biomembranes | ELSEVIER | Published : 2017
The formulation glatiramer acetate (GA) is widely used in therapy of multiple sclerosis. GA consists of random copolymers of four amino acids, in ratios that produce a predominantly positive charge and an amphipathic character. With the extraordinary complexity of the drug, several pharmacological modes-of-action were suggested, but so far none, which rationalizes the cationicity and amphipathicity as part of the mode-of-action. Here, we report that GA rapidly kills primary human T lymphocytes and, less actively, monocytes. LL-37 is a cleavage product of human cathelicidin with important roles in innate immunity. It shares the positive charge and amphipathic character of GA, and, as shown he..View full abstract
Awarded by Danish Multiple Sclerosis Association
Awarded by Novo Nordisk Foundation
The work was generously supported by grants from the Danish Multiple Sclerosis Association (R192-A10117-B143, R266-A14659-B143 & R308-A19315-B143) and The Novo Nordisk Foundation (R179-A15255). Our project was carried out in the context of The Lundbeck Foundation Nanomedicine Center for Individualized Management of Tissue Damage and Regeneration as well as the Center for Neurodegenerative Inflammation Prevention and MEMBRANES Research Center supported by the Aarhus University Research Foundation. We thank Professor Finn Sellebjerg, Rigshospitalet, University of Copenhagen, and Dr. Thor Petersen, Aarhus University Hospital for inspiration. We thank Professor Bent W. Deleuran and Dr. Halldor Bjarki Einarsson, Aarhus University Hospital, for helpful comments and Bettina W. Grumsen for excellent technical assistance in designing and executing the experiments. The FACS Core Facility within Dept. of Biomedicine, Aarhus University, is kindly acknowledged for their help in analyzing data.