Animal Models of Multiple Sclerosis

Smith, Paul A.

doi:10.1002/cpz1.185

Cited by 14 publications

(9 citation statements)

References 233 publications

(198 reference statements)

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“…Animal models with high translational validity are essential tools in understanding disease pathogenesis and in the development of therapeutic strategies. Currently, several animal models are mentioned, including Theiler's murine encephalomyelitis virus and cuprizone-induced demyelination [49][50][51]. Although no single animal model accurately reflects the complexity of human MS pathogenesis, EAE is the model which better reflects the autoimmune pathogenesis of MS and is extremely helpful to facilitate the study of pathogen-induced CNS autoimmunity, remyelination and other potential therapeutic strategies [52].…”

Section: Discussionmentioning

confidence: 99%

The epigenetic roles of BET inhibitors JQ1 and I-BET726 in regulating inflammation and treatment for experimental autoimmune encephalomyelitis

Li¹,

Zhang²,

Chen³

et al. 2023

Preprint

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The epigenetic factor bromodomain and extra-terminal domain (BET) proteins have multiple functions in regulating cell proliferation, differentiation and inflammation via binding to acetylated lysines on histones. JQ1 and I-BET726, new inhibitors of BET proteins, have potential therapeutic benefit for autoimmune diseases (AD). In this study, we explored the effects of JQ1 and I-BET726 on innate and adaptive immunity in experimental autoimmune encephalomyelitis (EAE) model to investigate the mechanism and therapeutic benefit for AD. The effects of JQ1 and I-BET726 on LPS-induced inflammation were investigated in innate and adaptive immune cells of dendritic cells (DCs), macrophages, and DC-dependent T cells. Different pro-inflammatory cytokines were assessed via real-time PCR, flow cytometry, and Elispot. Moreover, the effects of JQ1 and I-BET726 on EAE animals were further investigated, including the effects on alleviating clinical symptoms and inhibiting inflammation and demyelination in spinal cords via real-time PCR and immunohistochemical staining. JQ1 and I-BET726 efficiently inhibited LPS-increased TNF-α and IL-6 expression in bone marrow-derived DC and macrophage of Raw264.7 cells. They also suppressed adaptive immunity by down-regulating CD80/CD86 and IL-12/GM-CSF expressions, and inhibiting DC-dependent T cell priming. Moreover, they effectively inhibited TNF-α and IL-6 involved inflammatory changes in the spinal cords of EAE model, including inflammatory cell infiltration and demyelination. Most importantly, JQ1 and I-BET726 efficiently attenuated the clinical deterioration of EAE mice. Our results indicate that JQ1 and I-BET726 possess therapeutic benefits for autoimmune diseases by adjusting innate and adaptive immune response, indicating that BET bromodomain might be potential molecular targets for autoimmune disease therapy.

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Section: Discussionmentioning

confidence: 99%

The epigenetic roles of BET inhibitors JQ1 and I-BET726 in regulating inflammation and treatment for experimental autoimmune encephalomyelitis

Li¹,

Zhang²,

Chen³

et al. 2023

Preprint

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“…First, we established the demyelinating model. Cuprizone (CPZ) is a copper ion chelator that can demyelinate multiple structures in the CNS by inducing OL death [17]. It is commonly used to investigate the mechanisms of demyelination [18].…”

Section: Discussionmentioning

confidence: 99%

DAPT improves behavioral abnormalities and rescues the hippocampal Oligodendrocyte precursor cell differentiation in cuprizone-induceddemyelination mouse model

Chen

Cheng

et al. 2023

Preprint

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Introduction: Oligodendrocyte precursor cells (OPCs) differentiation dysfunction is closely related to demyelinating diseases and cognitive dysfunction. P75 neurotrophin receptor (P75NTR) is a prototypical co-receptor that induces Schwann cell death via γ-secretase-dependent regulated intramembrane proteolysis. This study hypothesizes that P75NTR may also assists in inhibiting OPCs differentiation.Methods Male C57BL/6 mice were fed 0.2% cuprizone (CPZ) continuously for 6 weeks to establish the acute demyelinating model (CPZ mice). Morris Water Maze and Elevated Plus Maze tests were used to assess the behavioral changes of these mice. Immunohistochemistry and Western blot were used to detect the OPCs and oligodendrocytes (OLs) protein markers. Furthermore, γ-secretase inhibitor DAPT (GSI-IX) was injected into the hippocampus at the fifth week of establishing the demyelinating model to investigate the effects of DAPT on OPCs differentiation and the mice’s behavioral changes.Results CPZ mice performed abnormal behavioral changes, and the protein expression of the OLs marker 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) decreased. However, the OPCs marker neural/glial antigen 2 (NG2) protein expression increased. After DAPT treatment, the abnormal behavior improved, CNPase increased, and NG2 decreased.Conclusions P75 cleavage plays an inhibitory role during the OPCs differentiation resulting in inefficient OPCs differentiation and recurrent demyelinating diseases.

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“…Mice were specific pathogen free and maintained in individually ventilated cages with a 12/12 h light/dark cycle. For induction of EAE female C57BL/6 mice of matched age and weight (Harlan, Switzerland or Envigo, Switzerland) were immunized as previously described [ 32 – 34 ]. Briefly, mice received a subcutaneous injection of recombinant human MOG (amino acids 30–149, produced in house) or recombinant rat MOG (amino acids 28–152, produced in house) emulsified in complete Freund adjuvant (Sigma, Switzerland) for huMOG EAE and for rat MOG EAE, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…In C57BL/6 mice variants of myelin oligodendrocyte glycoprotein (MOG)-induced EAE have been described, depending on whether the human (HuMOG) or rat (RatMOG) recombinant protein sequences are used for immunization [ 30 , 31 ]. Minor amino acid residue differences result in HuMOG-induced EAE being B cell dependent as the main APC, while RatMOG-induced EAE is B cell independent and requires dendritic cells as the dominant APC [ 32 ]. Given the role of BTK in B cells and the sensitivity of the HuMOG model to anti-CD20 depletion [ 33 ], we selected this model to asses B cell-dependent remibrutinib efficacy.…”

Section: Introductionmentioning

confidence: 99%

Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis

Nuesslein-Hildesheim,

Ferrero,

Schmid

et al. 2023

J Neuroinflammation

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Background Bruton’s tyrosine kinase (BTK) is a key signaling node in B cell receptor (BCR) and Fc receptor (FcR) signaling. BTK inhibitors (BTKi) are an emerging oral treatment option for patients suffering from multiple sclerosis (MS). Remibrutinib (LOU064) is a potent, highly selective covalent BTKi with a promising preclinical and clinical profile for MS and other autoimmune or autoallergic indications. Methods The efficacy and mechanism of action of remibrutinib was assessed in two different experimental autoimmune encephalomyelitis (EAE) mouse models for MS. The impact of remibrutinib on B cell-driven EAE pathology was determined after immunization with human myelin oligodendrocyte glycoprotein (HuMOG). The efficacy on myeloid cell and microglia driven neuroinflammation was determined in the RatMOG EAE. In addition, we assessed the relationship of efficacy to BTK occupancy in tissue, ex vivo T cell response, as well as single cell RNA-sequencing (scRNA-seq) in brain and spinal cord tissue. Results Remibrutinib inhibited B cell-dependent HuMOG EAE in dose-dependent manner and strongly reduced neurological symptoms. At the efficacious oral dose of 30 mg/kg, remibrutinib showed strong BTK occupancy in the peripheral immune organs and in the brain of EAE mice. Ex vivo MOG-specific T cell recall response was reduced, but not polyclonal T cell response, indicating absence of non-specific T cell inhibition. Remibrutinib also inhibited RatMOG EAE, suggesting that myeloid cell and microglia inhibition contribute to its efficacy in EAE. Remibrutinib did not reduce B cells, total Ig levels nor MOG-specific antibody response. In brain and spinal cord tissue a clear anti-inflammatory effect in microglia was detected by scRNA-seq. Finally, remibrutinib showed potent inhibition of in vitro immune complex-driven inflammatory response in human microglia. Conclusion Remibrutinib inhibited EAE models by a two-pronged mechanism based on inhibition of pathogenic B cell autoreactivity, as well as direct anti-inflammatory effects in microglia. Remibrutinib showed efficacy in both models in absence of direct B cell depletion, broad T cell inhibition or reduction of total Ig levels. These findings support the view that remibrutinib may represent a novel treatment option for patients with MS.

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Animal Models of Multiple Sclerosis

Cited by 14 publications

References 233 publications

The epigenetic roles of BET inhibitors JQ1 and I-BET726 in regulating inflammation and treatment for experimental autoimmune encephalomyelitis

The epigenetic roles of BET inhibitors JQ1 and I-BET726 in regulating inflammation and treatment for experimental autoimmune encephalomyelitis

DAPT improves behavioral abnormalities and rescues the hippocampal Oligodendrocyte precursor cell differentiation in cuprizone-induceddemyelination mouse model

Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis

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