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Mycophenolate mofetil prevents the delayed T cell response after pilocarpine-induced status epilepticus in mice.

Mycophenolate mofetil prevents the delayed T cell response after pilocarpine-induced status epilepticus in mice.
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Neumann AM, Abele J, Kirschstein T, Engelmann R, Sellmann T, Köhling R, Müller-Hilke B,


Neumann AM, Abele J, Kirschstein T, Engelmann R, Sellmann T, Köhling R, Müller-Hilke B, (click to view)

Neumann AM, Abele J, Kirschstein T, Engelmann R, Sellmann T, Köhling R, Müller-Hilke B,

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PloS one 2017 11 2812(11) e0187330 doi 10.1371/journal.pone.0187330

Abstract

Growing clinical and laboratory evidence corroborates a role for the immune system in the pathophysiology of epilepsy. In order to delineate the immune response following pilocarpine-induced status epilepticus (SE) in the mouse, we monitored the kinetics of leukocyte presence in the hippocampus over the period of four weeks. SE was induced following a ramping protocol of pilocarpine injection into 4-5 weeks old C57BL/6 mice. Brains were removed at days 1-4, 14 or 28 after SE, and the hippocampi were analyzed via flow cytometry, via quantitative reverse transcriptase PCR (qRT-PCR) and via immunohistochemistry. Epileptogenesis was confirmed by Timm staining of mossy fiber sprouting in the inner molecular layer of the dentate gyrus. The flow cytometry data revealed a biphasic immune response following pilocarpine-induced SE with a transient increase in activated CD11b+ and F4/80+ macrophages within the first four days replaced by an increase in CD3+ T-lymphocytes around day 28. This delayed T cell response was confirmed via qRT-PCR and via immunohistochemistry. In addition, qRT-PCR data could show that the delayed T cell response was associated with an increased CD8/CD4 ratio indicating a cytotoxic T cell response after SE. Intriguingly, early intervention with mycophenolate mofetil administration on days 0-3 after SE prevented this delayed T cell response. These results show an orchestrated immunological sequela and provide evidence that the delayed T cell response is sensitive to early immunomodulatory intervention.

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