Glatiramer acetate attenuates pro-inflammatory T cell responses but does not directly protect neurons from inflammatory cell death

Alexander M. Herrmann, Kerstin Göbel, Ole J. Simon, Nico Melzer, Michael K. Schuhmann, Max Philipp Stenner, Andreas Weishaupt, Christoph Kleinschnitz, Stefan Bittner, Patrick Meuth, Olaf Stuve, Thomas Budde, Bernd C. Kieseier, Heinz Wiendl, Sven G. Meuth

Research output: Contribution to journalArticle

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Abstract

Glatiramer acetate (GA) is a synthetic, random, basic copolymer capable of modulating adaptive T cell responses. In animal models of various inflammatory and degenerative central nervous system disorders, GA-induced T cells cross the blood-brain barrier, secrete high levels of anti-inflammatory cytokines and neurotrophins, and thus both reduce neuronal damage and promote neurogenesis. Recently, it has been suggested that GA itself may permeate the (impaired) blood-brain-barrier and directly protect neurons under conditions of inflammation-mediated neurodegeneration. To test this hypothesis, we examined the direct effects of GA on neuronal functionality and T cell-mediated neuronal apoptosis in culture, acute brain slices, and focal experimental autoimmune encephalomyelitis. GA caused a depolarization of the resting membrane potential and led to an immediate impairment of action potential generation in neurons. Moreover, GA-incubated neurons underwent dose-dependent apoptosis. Apoptosis of ovalbumin peptide-loaded major histocompatibility complex class I-expressing neurons induced by ovalbumin-specific effector T cells could be reduced by pre-incubation of T cells, but not neurons with GA. Similar results could be found using acute brain slices. In focal experimental autoimmune encephalomyelitis, lesion size and neuronal apoptosis could be limited by pretreating rats with GA, whereas intracerebral GA application into the inflammatory lesion had no effect on neuronal survival. Our data suggest that GA attenuates adaptive pro-inflammatory T cell responses, but does not exert direct neuroprotective effects.

Original languageEnglish (US)
Pages (from-to)3051-3060
Number of pages10
JournalAmerican Journal of Pathology
Volume177
Issue number6
DOIs
StatePublished - Dec 2010

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Cell Death
T-Lymphocytes
Neurons
Apoptosis
Autoimmune Experimental Encephalomyelitis
Ovalbumin
Blood-Brain Barrier
Glatiramer Acetate
Central Nervous System Diseases
Neurogenesis
Nerve Growth Factors
Brain
Neuroprotective Agents
Major Histocompatibility Complex
Membrane Potentials
Action Potentials
Anti-Inflammatory Agents
Animal Models
Cytokines
Inflammation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Herrmann, A. M., Göbel, K., Simon, O. J., Melzer, N., Schuhmann, M. K., Stenner, M. P., ... Meuth, S. G. (2010). Glatiramer acetate attenuates pro-inflammatory T cell responses but does not directly protect neurons from inflammatory cell death. American Journal of Pathology, 177(6), 3051-3060. https://doi.org/10.2353/ajpath.2010.100442

Glatiramer acetate attenuates pro-inflammatory T cell responses but does not directly protect neurons from inflammatory cell death. / Herrmann, Alexander M.; Göbel, Kerstin; Simon, Ole J.; Melzer, Nico; Schuhmann, Michael K.; Stenner, Max Philipp; Weishaupt, Andreas; Kleinschnitz, Christoph; Bittner, Stefan; Meuth, Patrick; Stuve, Olaf; Budde, Thomas; Kieseier, Bernd C.; Wiendl, Heinz; Meuth, Sven G.

In: American Journal of Pathology, Vol. 177, No. 6, 12.2010, p. 3051-3060.

Research output: Contribution to journalArticle

Herrmann, AM, Göbel, K, Simon, OJ, Melzer, N, Schuhmann, MK, Stenner, MP, Weishaupt, A, Kleinschnitz, C, Bittner, S, Meuth, P, Stuve, O, Budde, T, Kieseier, BC, Wiendl, H & Meuth, SG 2010, 'Glatiramer acetate attenuates pro-inflammatory T cell responses but does not directly protect neurons from inflammatory cell death', American Journal of Pathology, vol. 177, no. 6, pp. 3051-3060. https://doi.org/10.2353/ajpath.2010.100442
Herrmann, Alexander M. ; Göbel, Kerstin ; Simon, Ole J. ; Melzer, Nico ; Schuhmann, Michael K. ; Stenner, Max Philipp ; Weishaupt, Andreas ; Kleinschnitz, Christoph ; Bittner, Stefan ; Meuth, Patrick ; Stuve, Olaf ; Budde, Thomas ; Kieseier, Bernd C. ; Wiendl, Heinz ; Meuth, Sven G. / Glatiramer acetate attenuates pro-inflammatory T cell responses but does not directly protect neurons from inflammatory cell death. In: American Journal of Pathology. 2010 ; Vol. 177, No. 6. pp. 3051-3060.
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