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

PLoS One. 2017 Nov 28;12(11):e0187330. doi: 10.1371/journal.pone.0187330. eCollection 2017.

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.

MeSH terms

  • Animals
  • Immunophenotyping
  • Mice
  • Mice, Inbred C57BL
  • Mycophenolic Acid / pharmacology*
  • Pilocarpine / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Status Epilepticus / chemically induced*
  • Status Epilepticus / immunology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology

Substances

  • Pilocarpine
  • Mycophenolic Acid

Grants and funding

This study was funded by grants from Medical Faculty of the University of Rostock (FORUN grants no. 889026/2011 and 889026/2012 to TK and BMH). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.