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

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...

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Bibliographic Details
Published in:PloS one 2017-11, Vol.12 (11), p.e0187330-e0187330
Main Authors: Neumann, Anne-Marie, Abele, Julia, Kirschstein, Timo, Engelmann, Robby, Sellmann, Tina, Köhling, Rüdiger, Müller-Hilke, Brigitte
Format: Article
Language:English
Subjects:
Analysis
Animals
Biology and Life Sciences
Brain
CD11b antigen
CD3 antigen
CD4 antigen
CD8 antigen
Complications and side effects
Convulsions & seizures
Cytokines
Cytometry
Cytotoxicity
Dentate gyrus
Dosage and administration
Drug therapy
Encephalitis
Epilepsy
Flow cytometry
Gene expression
Genetic aspects
Hippocampus
Immune response
Immune system
Immunohistochemistry
Immunology
Immunomodulation
Inflammation
Intervention
Kinetics
Leukocytes
Lymphocytes
Lymphocytes T
Macrophages
Medicine and Health Sciences
Mice
Mycophenolate mofetil
Mycophenolic acid
Physiological aspects
Physiology
Pilocarpine
Research and Analysis Methods
RNA-directed DNA polymerase
Status epilepticus
T cells
Viral infections
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0187330