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Thomas Vorup-Jensen

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

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The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage. / Christiansen, Stig Hill; Zhang, Xianwei; Juul-Madsen, Kristian; Hvam, Michael Lykke; Vad, Brian Stougaard; Behrens, Manja Annette; Thygesen, Ida Lysgaard; Jalilian, Babak; Pedersen, Jan Skov; Howard, Ken; Otzen, Daniel E; Vorup-Jensen, Thomas.

I: B B A - Biomembranes, Bind 1859, Nr. 3, 03.2017, s. 425-437.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Christiansen, Stig Hill ; Zhang, Xianwei ; Juul-Madsen, Kristian ; Hvam, Michael Lykke ; Vad, Brian Stougaard ; Behrens, Manja Annette ; Thygesen, Ida Lysgaard ; Jalilian, Babak ; Pedersen, Jan Skov ; Howard, Ken ; Otzen, Daniel E ; Vorup-Jensen, Thomas. / The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage. I: B B A - Biomembranes. 2017 ; Bind 1859, Nr. 3. s. 425-437.

Bibtex

@article{f0996fd9623c481fbefd6d4746f2a3ad,
title = "The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage",
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.",
author = "Christiansen, {Stig Hill} and Xianwei Zhang and Kristian Juul-Madsen and Hvam, {Michael Lykke} and Vad, {Brian Stougaard} and Behrens, {Manja Annette} and Thygesen, {Ida Lysgaard} and Babak Jalilian and Pedersen, {Jan Skov} and Ken Howard and Otzen, {Daniel E} and Thomas Vorup-Jensen",
note = "Copyright {\circledC} 2017 Elsevier B.V. All rights reserved.",
year = "2017",
month = "3",
doi = "10.1016/j.bbamem.2017.01.001",
language = "English",
volume = "1859",
pages = "425--437",
journal = "B B A - Biomembranes",
issn = "0005-2736",
publisher = "Elsevier BV",
number = "3",

}

RIS

TY - JOUR

T1 - The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage

AU - Christiansen, Stig Hill

AU - Zhang, Xianwei

AU - Juul-Madsen, Kristian

AU - Hvam, Michael Lykke

AU - Vad, Brian Stougaard

AU - Behrens, Manja Annette

AU - Thygesen, Ida Lysgaard

AU - Jalilian, Babak

AU - Pedersen, Jan Skov

AU - Howard, Ken

AU - Otzen, Daniel E

AU - Vorup-Jensen, Thomas

N1 - Copyright © 2017 Elsevier B.V. All rights reserved.

PY - 2017/3

Y1 - 2017/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.bbamem.2017.01.001

DO - 10.1016/j.bbamem.2017.01.001

M3 - Journal article

C2 - 28064019

VL - 1859

SP - 425

EP - 437

JO - B B A - Biomembranes

JF - B B A - Biomembranes

SN - 0005-2736

IS - 3

ER -