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Biochim Biophys Acta. 2017 Mar;1859(3):425-437. doi: 10.1016/j.bbamem.2017.01.001. Epub 2017 Jan 5.

The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage.

Author information

1
Dept. of Biomedicine, Aarhus University, The Bartholin Building (1240), Bartholins Allé 6, DK-8000 Aarhus C, Denmark. Electronic address: stig.hill@biomed.au.dk.
2
Dept. of Biomedicine, Aarhus University, The Bartholin Building (1240), Bartholins Allé 6, DK-8000 Aarhus C, Denmark. Electronic address: xianwei.zhang@biomed.au.dk.
3
Dept. of Biomedicine, Aarhus University, The Bartholin Building (1240), Bartholins Allé 6, DK-8000 Aarhus C, Denmark. Electronic address: juul-madsen@biomed.au.dk.
4
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. Electronic address: mhvam@inano.au.dk.
5
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. Electronic address: bsv@chem.au.dk.
6
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. Electronic address: mab@inano.au.dk.
7
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark; Dept. of Micro- and Nanotechnology, Technical University of Denmark, Ørsteds Plads, Building 345C, DK-2800 Kgs. Lyngby, Denmark. Electronic address: idathyge@gmail.com.
8
Dept. of Biomedicine, Aarhus University, The Bartholin Building (1240), Bartholins Allé 6, DK-8000 Aarhus C, Denmark. Electronic address: jalilian.b@gmail.com.
9
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. Electronic address: jsp@chem.au.dk.
10
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark; The Lundbeck Foundation Nanomedicine Center for Individualized Management of Tissue Damage and Regeneration (LUNA), Aarhus University, Denmark. Electronic address: kenh@inano.au.dk.
11
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. Electronic address: dao@inano.au.dk.
12
Dept. of Biomedicine, Aarhus University, The Bartholin Building (1240), Bartholins Allé 6, DK-8000 Aarhus C, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark; The Lundbeck Foundation Nanomedicine Center for Individualized Management of Tissue Damage and Regeneration (LUNA), Aarhus University, Denmark; MEMBRANES Research Center, Aarhus University, Denmark; Center for Neurodegenerative Inflammation Prevention (NEURODIN), Aarhus University, Denmark. Electronic address: vorup-jensen@biomed.au.dk.

Abstract

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 here, also the ability to kill human leukocyte. The cytotoxicity of both compounds depends on sialic acid in the cell membrane. The killing was associated with the generation of CD45+ debris, derived from cell membrane deformation. Nanoparticle tracking analysis confirmed the formation of such debris, even at low GA concentrations. Electric cell-substrate impedance sensing measurements also recorded stable alterations in T lymphocytes following such treatment. LL-37 forms oligomers through weak hydrophobic contacts, which is critical for the lytic properties. In our study, SAXS showed that GA also forms this type of contacts. Taken together, our study offers new insight on the immunomodulatory mode-of-action of positively charged co-polymers. The comparison of LL-37 and GA highlights a consistent requirement of certain oligomeric and chemical properties to support cytotoxic effects of cationic polymers targeting human leukocytes.

KEYWORDS:

Cathelicidins; Cationic co-polymers; Glatiramoids; Immunotherapy

PMID:
28064019
DOI:
10.1016/j.bbamem.2017.01.001
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