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Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
Siponimod inhibits disease-associated microglia-T cell interactions in chronic experimental autoimmune
Leila Husseini1,2, Anastasia Geladaris3,2, Marlene C J Steinleitner1
1Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
Abstract:
Chronically inflamed, reactive microglia represent a prominent feature of secondary progressive multiple sclerosis (SPMS). Especially their interplay with encephalitogenic T cells promotes neuroaxonal damage associated with disease progression. In our study, we aimed to explore the potential of siponimod, a sphingosine-1-phosphate modulator approved for the treatment of active SPMS, to inhibit disease-associated T cell-microglia interactions using a chronic murine experimental autoimmune encephalomyelitis (EAE) model of MS. We found that therapeutic siponimod treatment of chronic EAE improved clinical severity accompanied by reduced demyelination and neuroaxonal damage, diminished CNS T cell infiltration and altered proinflammatory microglia responses. This effect was partly attributed to a direct effect on microglia, as siponimod pretreatment inhibited interferon-γ-elicited responses of primary mouse microglia in vitro and limited their ability to induce T cell activation and proliferation in T cell-microglia co-cultures. Additionally, we observed reduced peripheral T cell numbers in our EAE model, with a pronounced shift to immunosenescent and regulatory T cell subsets, a pattern which we similarly detected in a cohort of SPMS patients following siponimod treatment. These findings indicate that siponimod dampens compartmentalized CNS inflammation by disrupting detrimental interactions between T cells and microglia through a dual central and peripheral mechanism of action.
Insights
Siponimod treatment reduced disease severity in a multiple sclerosis model by inhibiting harmful T cell-microglia interactions. This drug dampens central nervous system inflammation through both direct effects on microglia and by altering peripheral T cell populations.
Area of Science:
- Neuroimmunology
- Pharmacology
Background:
- Microglia are key players in chronic inflammation in secondary progressive multiple sclerosis (SPMS).
- The interaction between microglia and T cells exacerbates neuroaxonal damage in SPMS.
Purpose of the Study:
- To investigate siponimod's potential to inhibit T cell-microglia interactions in a murine model of multiple sclerosis.
- To elucidate siponimod's mechanism of action in reducing central nervous system (CNS) inflammation.
Main Methods:
- Utilized a chronic experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.
- Assessed siponimod's therapeutic effects on clinical severity, demyelination, and neuroaxonal damage.
- Investigated siponimod's direct effects on primary mouse microglia and T cell activation in vitro.
- Analyzed peripheral and CNS T cell populations in EAE mice and SPMS patients.
Main Results:
- Siponimod treatment improved clinical outcomes in chronic EAE, reducing demyelination and neuroaxonal damage.
- Siponimod inhibited T cell infiltration into the CNS and modulated proinflammatory microglia responses.
- In vitro studies showed siponimod directly inhibited microglia activation and their ability to stimulate T cells.
- Siponimod treatment led to reduced peripheral T cell numbers, with a shift towards immunosenescent and regulatory T cells, mirroring findings in SPMS patients.
Conclusions:
- Siponimod effectively dampens CNS inflammation in experimental autoimmune encephalomyelitis.
- The drug acts through a dual mechanism, affecting both central microglia-T cell interactions and peripheral T cell populations.
- These findings support siponimod's role in managing SPMS by disrupting detrimental neuroinflammatory pathways.
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