Abstract
BackgroundInhalational anesthetics have been shown to influence T cell functions both in vitro and in vivo, in many cases inducing T cell death, suggesting that exposure to these drugs could modify the course of an autoimmune disease. We tested the hypothesis that in mice immunized to develop experimental autoimmune encephalomyelitis (EAE), a well established model of multiple sclerosis (MS), treatment with the commonly used inhalational anesthetic sevoflurane would attenuate disease symptoms.MethodsC57Bl6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide residues 35 to 55 to induce a chronic demyelinating disease. At day 10 after immunization, the mice were subjected to 2 h of 2.5% sevoflurane in 100% oxygen, or 100% oxygen, alone. Following treatment, clinical scores were monitored up to 4 weeks, after which brain histology was performed to measure the effects on astrocyte activation and lymphocyte infiltration. Effects of sevoflurane on T cell activation were studied using splenic T cells isolated from MOG peptide-immunized mice, restimulated ex vivo with MOG peptide or with antibodies to CD3 and CD28, and in the presence of different concentrations of sevoflurane. T cell responses were assessed 1 day later by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for proliferation, lactate dehydrogenase (LDH) release for cell death, and inflammatory activation by production of interleukin (IL)-17 and interferon (IFN)γ.ResultsClinical scores in the oxygen-treated group increased until day 28 at which time they showed moderate to severe disease (average clinical score of 2.9). In contrast, disease progression in the sevoflurane-treated group increased to 2.1 at day 25, after which it remained unchanged until the end of the study. Immunohistochemical analysis revealed reduced numbers of infiltrating leukocytes and CD4+ cells in the CNS of the sevoflurane-treated mice, as well as reduced glial cell activation. In splenic T cells, low doses of sevoflurane reduced IFNγ production, cell proliferation, and increased LDH release.ConclusionsThese results are the first to show attenuation of EAE disease by an inhaled anesthetic and are consistent with previous reports that inhaled anesthetics, including sevoflurane, can suppress T cell activation that, in the context of autoimmune diseases such as MS, could lead to reduced clinical progression.
Highlights
Inhalational anesthetics have been shown to influence T cell functions both in vitro and in vivo, in many cases inducing T cell death, suggesting that exposure to these drugs could modify the course of an autoimmune disease
The exact causes of multiple sclerosis (MS) are not yet precisely known, it is well established that activation of the adaptive immune system leads to activation and proliferation of T cells that can infiltrate the central nervous system and release cytokines that lead to oligodendrocyte damage, demyelination, and axonal damage
Sevoflurane attenuates development of clinical signs of EAE C57Bl6 mice were immunized with MOG35-55 peptide to develop a chronic demyelinating disease using a standardized protocol
Summary
Inhalational anesthetics have been shown to influence T cell functions both in vitro and in vivo, in many cases inducing T cell death, suggesting that exposure to these drugs could modify the course of an autoimmune disease. Sevoflurane increased caspase activation and apoptosis, altered amyloid precursor protein (APP) processing, and increased β-amyloid levels in the brains of transgenic mouse models of AD [1] and in APP-expressing cells [1,2]. These studies were based on observations that small molecular weight hydrophobic alkanes can shift oligomerization of proteins such as β-amyloid towards higher oligomers and increase cytotoxicity [3,4,5]. Several treatments which reduce T cell activation, proliferation, infiltration into the CNS, or cytokine production are currently used to reduce MS symptoms; additional non-invasive, safe methods to modulate T cell functions still have potential value for MS treatment
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