Understanding Multiple Sclerosis through EAE Mouse Models

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal damage. Experimental autoimmune encephalomyelitis (EAE) is the most widely used animal model for studying MS due to its resemblance to human pathology.

Creative Biolabs has continuously endeavored to shine a light on various disease models to expedite organizations' path to discovery and drug development. Here, we delve into the intricacies of EAE mouse models, exploring their significance, methodologies, challenges, and recent advancements.

In collaboration with Creative Biolabs, pioneering efforts continue to refine and innovate EAE models, enhancing their translational relevance and expanding their utility in preclinical research. By harnessing the power of cutting-edge technologies, such as humanized mouse models, advanced imaging modalities, and computational approaches, we are poised to unlock new insights into MS and pave the way for transformative therapies.

EAE Mouse Models: A Concrete Tool for MS Studies

Given its intricate nature, studying MS is a challenge that necessitates advanced, comprehensive models. Enter the EAE mouse models, among the most extensively used to grasp the underpinning of this perplexing disease.

Fig. 1 Schematic diagram of some of the key pathological features of EAE pathogenesis.¹

Introduced in the early 20th century, EAE models are still employed and refined due to their ability to replicate key aspects of human MS. Predominantly, they mimic MS's autoimmune aspects wherein the immune system is erroneously programmed to attack healthy myelin sheaths, the protective padding surrounding nerve fibers leading to inflammation and scar tissue. EAE mouse models effectively simulate critical characteristics of MS in humans, such as immune cell infiltration and neurological deficits, making them vital in understanding and treating this complex disease.

Induction of EAE in mice involves several key steps, each carefully designed to trigger an autoimmune response against CNS antigens.

• Central to EAE induction is the selection of appropriate antigenic targets, typically myelin proteins such as myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG). These antigens are emulsified in an adjuvant, such as complete Freund's adjuvant (CFA), to enhance immunogenicity and promote T cell activation.
• Subsequent administration of the antigen-adjuvant emulsion by intraperitoneal or subcutaneous injection initiates the immune system, leading to activation and expansion of CNS antigen-specific autoreactive T cells.
• Following immunization, mice are monitored for clinical signs of disease, including motor defects, gait abnormalities, and paralysis.

Below are some of the main EAE model types.

Applications of EAE Mouse Models

EAE mouse models help elucidate the cellular and molecular mechanisms underlying the pathogenesis of MS. By dissecting the complex interactions between immune cells, cytokines and the central nervous system microenvironment, researchers can identify new therapeutic targets for MS treatment.

• By utilizing EAE mouse models, researchers unearthed the pivotal role of T cells in mediating the immune response in MS. The EAE model showcased that Th17 and Th1 cells are quintessential for initiating MS and propelling its progression.
• The EAE model has elucidated the involvement of the blood-brain barrier (BBB) disruption in MS.
• EAE models have showcased MOG as a crucial autoantigen initiating the autoimmune response in MS.

Below is a summary of commonly used targets for MS.

We provide relevant research tools for these targets.

The EAE mouse model is a valuable tool for preclinical drug testing and screening. Candidate therapies can be evaluated for their efficacy in reducing inflammation, maintaining myelin integrity and preventing neuronal damage, paving the way for the development of new MS therapies.

• Using the EAE model, Fingolimod, a sphingosine-1-phosphate receptor modulator, was tested, which led to its FDA approval as the first oral treatment for relapsing forms of MS.

Many of the currently approved therapies for MS disease remission were initially validated in EAE mouse models. The EAE mouse model also provides insights into potential regenerative strategies aimed at restoring damaged myelin and promoting neuronal repair.

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Advancements in EAE Mouse Model Research

• Precision Medicine Approaches: By introducing targeted mutations or transgene constructs, these models better recapitulate the genetic heterogeneity observed in human MS populations.
• Microbiome Influence: EAE mouse models provide a platform for studying the interactions between gut microbes, the immune system, and CNS autoimmunity, offering new avenues for therapeutic intervention.
• Neuroinflammation Imaging: Non-invasive imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) enable longitudinal monitoring of neuroinflammatory processes in live EAE mice.
• Cell Therapy Optimization: Recent studies have focused on optimizing cell-based therapies for MS using EAE mouse models. Mesenchymal stem cells (MSCs), regulatory T cells (Tregs), and other immune-modulating cell types show promise in attenuating EAE symptoms and promoting tissue repair.

No model is flawless, and EAE models are no exception. Whilst they replicate numerous aspects of human MS, they do not cover the entire spectrum of this intricate disorder. Therefore, scientists continue to refine and develop novel EAE models that emulate various aspects and forms of MS with greater accuracy. Offering bespoke services and resources, Creative Biolabs aims to accelerate research and therapeutic development, one successful model at a time.

Reference

1. Constantinescu, Cris S., et al. "Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)." British journal of pharmacology 164.4 (2011): 1079-1106.

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