Rodent Experimental Autoimmune Encephalomyelitis Research Articles

Proinflammatory CD20+ T cells contribute to CNS-directed autoimmunity.

The origin and function of CD20+ T cells are poorly understood. Here, we characterized CD20+ T cells in mice and humans and investigated how they are affected by anti-CD20 antibody treatment. We report that murine CD20+ T cells are unable to endogenously express the B cell lineage marker CD20; the development of CD20+ T cells in rodents requires the presence of CD20-expressing B cells. Our results demonstrated that both murine and human T cells acquire CD20 from B cells via trogocytosis while being activated by an antigen-presenting B cell. In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), expression of CD20 on T cells is associated with an up-regulation of activation markers, proinflammatory cytokines, and adhesion molecules, suggesting high pathogenic potential. Supporting this hypothesis, CD20+ T cells expand during active EAE in rodents; furthermore, adoptive transfer of CD20+ T cells into EAE-diseased mice worsened histological and clinical severity. Of direct therapeutic relevance, we demonstrate that the exclusive therapeutic elimination of CD20+ T cells effectively ameliorates EAE, independent of B cells. The results support the hypothesis that CD20+ T cells arise upon B cell-T cell interaction and that depletion of CD20+ T cells might contribute to the success of anti-CD20 antibody therapies in MS and other inflammatory disorders.

Lipid Receptor G2A-Mediated Signal Pathway Plays a Critical Role in Inflammatory Response by Promoting Classical Macrophage Activation.

Macrophage polarization is a dynamic and integral process in tissue inflammation and remodeling. In this study, we describe that lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an important role in controlling inflammatory macrophage (M1) polarization in rodent experimental autoimmune encephalomyelitis (EAE) and in monocytes from multiple sclerosis (MS) patients. Specific inhibition of Lp-PLA2 led to an ameliorated EAE via markedly decreased inflammatory and demyelinating property of M1. The effects of Lp-PLA2 on M1 function were mediated by lysophosphatidylcholine, a bioactive product of oxidized lipids hydrolyzed by Lp-PLA2 through JAK2-independent activation of STAT5 and upregulation of IRF5. This process was directed by the G2A receptor, which was only found in differentiated M1 or monocytes from MS patients. M1 polarization could be inhibited by a G2A neutralizing Ab, which led to an inhibited disease in rat EAE. In addition, G2A-deficient rats showed an ameliorated EAE and an inhibited autoimmune response. This study has revealed a mechanism by which lipid metabolites control macrophage activation and function, modification of which could lead to a new therapeutic approach for MS and other inflammatory disorders.

Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen-a marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.

Experimental Autoimmune Encephalomyelitis (EAE) Model of Cynomolgus Macaques Induced by Recombinant Human MOG1-125 (rhMOG1-125) Protein and MOG34-56 Peptide.

Experimental autoimmune encephalomyelitis (EAE) induced by self-myelin antigen is a widely used in multiple sclerosis (MS) model for preclinical studies of new therapeutics and potential pathogenesis. By comparison with rodent EAE models, EAE models in primates are more similar to MS. Some groups have developed EAE models in primates by using common marmoset (Callithrix jacchus). However, this model has some limitations. EAE in cynomolgus monkey (Macaque fasciculrais) could overcome these limitations. The main objective of this study was to establish an ideal EAE cynomolgus monkey model resembling human MS by immunizing human myelin oligodendrocyte glycoprotein (MOG) protein. In this study, six female cynomolgus monkeys were divided into two separate experiment groups and one monkey as the control. EAE was induced in cynomolgus monkey by immunizing with the recombinant human myelin oligodendrocyte glycoprotein extracellular domain (1-125) (rhMOG1-125) and a synthetic peptide, representing peptide 34-56 of human myelin oligodendrocyte glycoprotein (MOG34-56) in complete Freund's adjuvant (CFA) by subcutaneous multipoint immunization in the armpit and inguinal region and in combination with intravenous injection of pertussis toxin, and subsequent booster immunizations with the same dose of antigen in incomplete Freund's adjuvant (IFA) until the animals developed clinically significant EAE (score≥2). The body weight, clinical scores, magnetic resonance imaging (MRI), histopathology, antibody, cytokine profiling and antigen-specific lymphocyte proliferation were evaluated. The results showed that despite the different time intervals between onset and significant neurological deficits, all the cynomolgus monkeys immunized with rhMOG1-125 or MOG34-56 developed clinically significant acute fulminant or mild forms of EAE, with a success rate of 100%. The clinical courses were obvious heterogeneity which closely resembles MS. MOG34-56 immunization was much milder compared with rhMOG1-125 immunized individuals, at least in cynomolgus monkeys. Inflammation and demyelinated lesions were present in the brains and spinal cords. Immune profiling revealed high IgG levels associated with early onset of EAE but not the course of the disease. Significant antigen-specific T lymphocyte responses against immunodominant epitopes of MOG were also detected. Our results indicated rhMOG1-125 and MOG34-56 could induce successfully EAE models resembling MS in cynomolgus monkeys. The synergistic action of anti-myelin T cells and Abs during the pathogenesis of EAE could establish a more ideal EAE model.

Severe oxidative stress in an acute inflammatory demyelinating model in the rhesus monkey.

Oxidative stress is increasingly implicated as a co-factor of tissue injury in inflammatory/demyelinating disorders of the central nervous system (CNS), such as multiple sclerosis (MS). While rodent experimental autoimmune encephalomyelitis (EAE) models diverge from human demyelinating disorders with respect to limited oxidative injury, we observed that in a non-human primate (NHP) model for MS, namely EAE in the common marmoset, key pathological features of the disease were recapitulated, including oxidative tissue injury. Here, we investigated the presence of oxidative injury in another NHP EAE model, i.e. in rhesus macaques, which yields an acute demyelinating disease, which may more closely resemble acute disseminated encephalomyelitis (ADEM) than MS. Rhesus monkey EAE diverges from marmoset EAE by abundant neutrophil recruitment into the CNS and destructive injury to white matter. This difference prompted us to investigate to which extent the oxidative pathway features elicited in MS and marmoset EAE are reflected in the acute rhesus monkey EAE model. The rhesus EAE brain was characterized by widespread demyelination and active lesions containing numerous phagocytic cells and to a lesser extent T cells. We observed induction of the oxidative stress pathway, including injury, with a predilection of p22phox expression in neutrophils and macrophages/microglia. In addition, changes in iron were observed. These results indicate that pathogenic mechanisms in the rhesus EAE model may differ from the marmoset EAE and MS brain due to the neutrophil involvement, but may in the end lead to similar induction of oxidative stress and injury.

Oxidative Injury and Iron Redistribution Are Pathological Hallmarks of Marmoset Experimental Autoimmune Encephalomyelitis.

Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2. The EAE lesion-associated liberation of iron (due to loss of iron-containing myelin) was associated with altered expression of the iron metabolic markers FtH1, lactoferrin, hephaestin, and ceruloplasmin. The enhanced expression of oxidative damage markers in inflammatory lesions indicates that the enhanced antioxidant enzyme expression could not counteract reactive oxygen and nitrogen species-induced cellular damage, as is also observed in MS brains. This study demonstrates that oxidative injury and aberrant iron distribution are prominent pathological hallmarks of marmoset EAE thus making this model suitable for therapeutic intervention studies aimed at reducing oxidative stress and associated iron dysmetabolism.

Novel Zebrafish EAE model: A quick in vivo screen for multiple sclerosis

IntroductionPre-clinical drug discovery for multiple sclerosis (MS) is a labor intensive activity to perform in rodent models. This is owing to the long duration of disease induction and observation of treatment effects in an experimental autoimmune encephalomyelitis (EAE) model. We propose a novel adult zebrafish based model which offers a quick and simple protocol that can used to screen candidates as a step between in vitro experiments and rodent studies. The experiments conducted for this manuscript were to standardize a suitable model of EAE in adult zebrafish and validate it using known modulators. MethodsThe EAE model was developed by disease induction with myelin oligodendrocyte glycoprotein – 35–55 (MOG) and observation of survival, clinical signs and body weight changes. We have validated this model using fingolimod. We have further performed detailed validation using dimethyl fumarate, dexamethasone and SR1001, which are known modulators of rodent EAE. ResultsThe immunization dose for the disease induction was observed to be 0.6mg/ml of MOG in CFA (Complete Freund's adjuvant), injected subcutaneously (s.c.) near spinal vertebrae. In the validation study with fingolimod, we have demonstrated the modulation of disease symptoms, which were also confirmed by histopathological evaluation. Furthermore, detailed validation with three other known drugs showed that our observations concur with those reported in conventional rodent models. DiscussionWe have standardized and validated the adult zebrafish EAE model. This model can help get a quick idea of in vivo activity of drugs in a week using very low quantities of candidate compounds. Further work will be required to define this model particularly as it is found that zebrafish may not express a MOG homologue.

The common marmoset as an indispensable animal model for immunotherapy development in multiple sclerosis

New drugs often fail in the translation from the rodent experimental autoimmune encephalomyelitis (EAE) model to human multiple sclerosis (MS). Here, we present the marmoset EAE model as an indispensable model for translational research into MS. The genetic heterogeneity of this species and lifelong exposure to chronic latent infections and environmental pathogens create a human-like immune system. Unique to this model is the presence of the pathological hallmark of progressive MS, in particular cortical grey matter lesions. Another great possibility of this model is systemic and longitudinal immune profiling, whereas in humans and mice immune profiling is usually performed in a single compartment (i.e. blood or spleen, respectively). Overall, the marmoset model provides unique opportunities for systemic drug-effect profiling.

Multiple rodent models and behavioral measures reveal unexpected responses to FTY720 and DMF in experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a widely-used rodent model for multiple sclerosis (MS), but a single model can hardly capture all features of MS. We investigated whether behavioral parameters in addition to clinical motor function scores could be used to assess treatment efficacy during score-free intervals in the relapsing-remitting EAE model in SJL/J mice. We studied the effects of the clinical reference compounds FTY720 (fingolimod, 0.5mg/kg/day) and dimethyl fumarate (DMF, 20–30mg/kg/day) on clinical scores in several rodent EAE models in order to generate efficacy profiles. SJL/J mice with relapsing-remitting EAE were studied using behavioral tests, including rotarod, gait analysis, locomotor activity and grip strength. SJL/J mice were also examined according to Crawley’s sociability and preference for social novelty test. Prophylactic treatment with FTY720 prevented clinical scores in three of the four EAE rodent models: Dark Agouti (DA) and Lewis rats and C57BL/6J mice. Neither prophylactic nor late-therapeutic treatment with FTY720 reduced clinical scores or reversed deficits in the rotarod test in SJL/J mice, but we observed effects on motor functions and sociability in the absence of clinical scores. Prophylactic treatment with FTY720 improved the gait of SJL/J mice whereas late-therapeutic treatment improved manifestations of reduced social (re)cognition or preference for social novelty. DMF was tested in three EAE models and did not improve clinical scores at the dose used. These data indicate that improvements in behavioral deficits can occur in absence of clinical scores, which indicate subtle drug effects and may have translational value for human MS.

ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile.

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of five G protein-coupled receptors (S1P1–S1P5). S1P1 is a major regulator of lymphocyte trafficking, and fingolimod, whose active metabolite fingolimod phosphate acts as a nonselective S1P receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating the lymphocyte trafficking by inducing down regulation of lymphocyte S1P1. Here, we detail the pharmacological profile of 5-{5-[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (ASP4058), a novel next-generation S1P receptor agonist selective for S1P1 and S1P5. ASP4058 preferentially activates S1P1 and S1P5 compared with S1P2, 3, 4 in GTPγS binding assays in vitro. Oral administration of ASP4058 reduced the number of peripheral lymphocytes and inhibited the development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Further, ASP4058 prevented relapse of disease in a mouse model of relapsing-remitting EAE. Although these immunomodulatory effects were comparable to those of fingolimod, ASP4058 showed a wider safety margin than fingolimod for bradycardia and bronchoconstriction in rodents. These observations suggest that ASP4058 represents a new therapeutic option for treating multiple sclerosis that is safer than nonselective S1P receptor agonists such as fingolimod.

N-Palmitoylethanolamine Administration Ameliorates the Clinical Manifestation and Progression of Experimental Autoimmune Encephalomyelitis in Rodents

Experimental autoimmune encephalomyelitis in rodents (EAE) is an accepted in vivo model for immunopathogenic mechanisms underlying multiple sclerosis (MS) and tests possible treatment options because it mimics many of the disease patterns. The current treatments for delaying MS progression include cytostatic, immunomodulatory drugs such as mitoxantrone, cyclophosphamide (CY), biological agents such as interferon (IFN)-beta, natalizumab and random polymer glatiramer acetate. Unfortunately, all of these compounds have potentially serious side effects, some require systemic administration, and the biological agents are costly and immunogenic, causing response failure during prolonged treatment. With this aim in mind, the purpose of the current research was to examine the effects of endogenous substances such as N-palmitoylethanolamine (PEA). PEA is an endogenous fatty acid amide belonging to the family of the N-acylethanolamines (NAEs). Recently, several studies demonstrated that PEA is an important analgesic, anti-inflammatory and neuroprotective mediator, acting at several molecular targets in both central and sensory nervous systems as well as immune cells. The effect of PEA daily administered was investigated in rats and mice developing EAE. A multidisciplinary approach was employed to study behavior and biochemical parameters. In our study we found that PEA counteracts the clinical course and pathology of monophasic EAE in myelin basic protein-immunized Lewis rats and the progression of EAE induced in C57BI/6 mice by immunization with myelin oligodendrocyte glycoprotein. Our results show that PEA treatment had a beneficial effect on the two different EAE models.

Kingdom-Agnostic Metagenomics and the Importance of Complete Characterization of Enteric Microbial Communities

Advanced sequencing techniques have shown that bacteria are not the only complex and important microbes in the human intestine. Nonbacterial organisms, particularly the virome and the mycobiome, are important regulators of intestinal immunity and inflammation. The virome is mucosal and systemic; it can alter the host response to bacteria and interact with host genes and bacteria to contribute to disease pathogenesis. The human mycobiome is also complex and can contribute to intestinal inflammation. We review what has recently been learned about the nonbacterial and nonarchaeal microbes in the gastrointestinal tract, discussing their potential effects on health and disease and analytical approaches for their study. Studies of associations between the microbiome and intestinal pathology should incorporate kingdom-agnostic approaches if we are to fully understand intestinal health and disease.

Multiple sclerosis-induced neuropathic pain: pharmacological management and pathophysiological insights from rodent EAE models.

In patients with multiple sclerosis (MS), pain is a frequent and disabling symptom. The prevalence is in the range 29–86 % depending upon the assessment protocols utilised and the definition of pain applied. Neuropathic pain that develops secondary to demyelination, neuroinflammation and axonal damage in the central nervous system is the most distressing and difficult type of pain to treat. Although dysaesthetic extremity pain, L’hermitte’s sign and trigeminal neuralgia are the most common neuropathic pain conditions reported by patients with MS, research directed at gaining insight into the complex mechanisms underpinning the pathobiology of MS-associated neuropathic pain is in its relative infancy. By contrast, there is a wealth of knowledge on the neurobiology of neuropathic pain induced by peripheral nerve injury. To date, the majority of research in the MS field has used rodent models of experimental autoimmune encephalomyelitis (EAE) as these models have many clinical and neuropathological features in common with those observed in patients with MS. However, it is only relatively recently that EAE-rodents have been utilised to investigate the mechanisms contributing to the development and maintenance of MS-associated central neuropathic pain. Importantly, EAE-rodent models exhibit pro-nociceptive behaviours predominantly in the lower extremities (tail and hindlimbs) as seen clinically in patients with MS-neuropathic pain. Herein, we review research to date on the pathophysiological mechanisms underpinning MS-associated neuropathic pain as well as the pharmacological management of this condition. We also identify knowledge gaps to guide future research in this important field.

Stem Cell Therapy for Multiple Sclerosis: Preclinical Evidence Beyond All Doubt?

Stem cell transplantation holds great promise for restoration of neural function in various neurodegenerative disorders, including multiple sclerosis (MS). However, many questions remain regarding the true efficacy and precise mode of action of stem cell-based therapeutic approaches. Therefore, in this article, we will first discuss the ideal route and/or timing of stem cell-based therapies for experimental autoimmune encephalomyelitis (EAE), the most used preclinical animal model for MS. Next, we will provide an overview of the proposed mechanisms that contribute to the beneficial effects of stem cell transplantation observed during the treatment of rodent EAE. Reviews of current and past literature clearly demonstrate conceptual changes in the development of stem cell-based approaches for EAE/MS, leading to the identification of several major challenges to be tackled before (stem) cell therapy for rodent EAE can be safely and successfully translated to human therapy for MS.

Erythropoietin Attenuates Neurological and Histological Consequences of Toxic Demyelination in Mice

Erythropoietin (EPO) reduces symptoms of experimental autoimmune encephalomyelitis in rodents and shows neuroregenerative effects in chronic progressive multiple sclerosis. The mechanisms of action of EPO in these conditions with shared immunological etiology are still unclear. Therefore, we used a model of toxic demyelination allowing exclusion of T cell-mediated inflammation. In a double-blind (for food/injections), placebo-controlled, longitudinal four-arm design, 8-wk-old C57BL/6 mice (n = 26/group) were assigned to cuprizone-containing (0.2%) or regular food (ground chow) for 6 wks. After 3 wks, mice were injected every other day with placebo or EPO (5,000 IU/kg intraperitoneally) until the end of cuprizone feeding. Half of the mice were exposed to behavioral testing, magnetic resonance imaging (MRI) and histology immediately after treatment cessation, whereas the other half were allowed a 3-wk treatment-free recovery. Immediately after termination of cuprizone feeding, all toxin-exposed mice were compromised regarding vestibulomotor function/coordination, with EPO-treated animals performing better than placebo. Likewise, ventricular enlargement after cuprizone, as documented by MRI, was less pronounced upon EPO. After a 3-wk recovery, remarkable spontaneous improvement was observed in all mice with no measurable further benefit in the EPO group ("ceiling effect"). Histological analysis of the corpus callosum revealed attenuation by EPO of the cuprizone-induced increase in microglial numbers and amyloid precursor protein accumulations as a readout of inflammation and axonal degeneration. To conclude, EPO ameliorates neurological symptoms in the cuprizone model of demyelination, possibly by reduction of inflammation-associated axonal degeneration in white matter tracts. These findings underscore the value of future therapeutic strategies for multiple sclerosis based on EPO or EPO variants.

0842 Myelin-oligodendrocyte glycoprotein antibody as a cause of acute disseminated encephalomyelitis with a neuromyelitis optica-like phenotype in adults

Neuromyelitis optica (NMO) is an autoimmune CNS disorder causing optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM). Limited forms of the disease are called NMO spectrum disorder (NMOSD). Disease...

Specific and Strain-Independent Effects of Dexamethasone in the Prevention and Treatment of Experimental Autoimmune Encephalomyelitis in Rodents

Experimental autoimmune encephalomyelitis in rodents (EAE) is a generally accepted in vivo model for immunopathogenic mechanisms underlying multiple sclerosis (MS). There are, however, different forms of rodent EAE, and therapeutic regimens may affect these forms differently. We have therefore tested the effects of dexamethasone (Dex) and found that both prophylactic and early therapeutic regimens were effective in suppressing the development of monophasic EAE in myelin basic protein-immunized Lewis rats, the relapsing-remitting forms of EAE induced in SJL mice by proteolipid protein and in DA rats by syngeneic spinal cord homogenate, and the progressive forms induced in C57BL/6 and DBA/1 mice by immunization with myelin oligodendrocyte glycoprotein. In addition, prophylactically administered Dex suppressed histological and immunological features of EAE such as spinal cord infiltration of inflammatory cells and the increased frequency of autoantigen-specific interferon-gamma-secreting lymph node mononuclear cells. The present data reproduced in rodent EAE models some of the beneficial effects observed with glucocorticoids in MS. This strengthens the validity of these five models as in vivo predictors of drug efficacy in at least some variants of human MS. Better understanding of the clinical and immunopharmacologic features of these models might prove useful when testing new drug candidates for MS treatment.

Experimental Autoimmune Encephalomyelitis in the Common Marmoset, a Bridge Between Rodent EAE and Multiple Sclerosis for Immunotherapy Development

The attrition rate of new drugs for central nervous system diseases including multiple sclerosis (MS) is very high. A widely recognized bottleneck in the selection of promising central nervous system drug candidates from the development pipeline is the lack of sufficiently predictive animal models. Here, we review how the experimental autoimmune encephalomyelitis (EAE) model in the Neotropical primate "common marmoset" can help to bridge the gap between rodent EAE models and MS. The EAE model in the marmoset closely resembles MS in the clinical as well as pathological presentation and can be used for fundamental research into immunopathogenic mechanisms and for therapy development. We discuss recent insights arising from this model, both on novel therapeutics and immunopathogenesis.

Pharmacotherapy with 17β-estradiol and progesterone prevents development of mouse experimental autoimmune encephalomyelitis.

Pregnant women with multiple sclerosis (MS) show disease remission in the third trimester concomitant with high circulating levels of sex steroids. Rodent experimental autoimmune encephalomyelitis (EAE) is an accepted model for MS. Previous studies have shown that monotherapy with estrogens or progesterone exert beneficial effects on EAE. The aim of the present study was to determine if estrogen and progesterone cotherapy of C57BL/6 female mice provided substantial protection from EAE. A group of mice received single pellets of progesterone (100mg) and 17 β-estradiol (2.5mg) subcutaneously 1week before EAE induction, whereas another group were untreated before EAE induction. On day 16 we compared the two EAE groups and control mice in terms of clinical scores, spinal cord demyelination, expression of myelin basic protein and proteolipid protein, macrophage cell infiltration, neuronal expression of brain-derived neurotrophic factor mRNA and protein, and the number of glial fribrillary acidic protein (GFAP)-immunopositive astrocytes. Clinical signs of EAE were substantially attenuated by estrogen and progesterone treatment. Steroid cotherapy prevented spinal cord demyelination, infiltration of inflammatory cells and GFAP+ astrogliocytes to a great extent. In motoneurons, expression of BDNF mRNA and protein was highly stimulated, indicating concomitant beneficial effects of the steroid on neuronal and glial cells. Cotherapy with estrogen and progesterone inhibits the development of major neurochemical abnormalities and clinical signs of EAE. We suggest that a combination of neuroprotective, promyelinating and immuno-suppressive mechanisms are involved in these beneficial effects.

Clinical, Pathological, and Immunologic Aspects of the Multiple Sclerosis Model in Common Marmosets (Callithrix jacchus)

The efficacy of many new immunomodulatory therapies for multiple sclerosis (MS) patients has often been disappointing, reflecting our incomplete understanding of this enigmatic disease. There is a growing awareness that, at least in part, there may be limited applicability to the human disease of results obtained in the widely studied MS model experimental autoimmune encephalomyelitis in rodents. This review describes the experimental autoimmune encephalomyelitis model developed in a small neotropical primate, the common marmoset (Callithrix jacchus). The model has features including clinicopathologic correlation patterns, lesion heterogeneity, immunologic mechanisms, and disease markers that more closely mimic the human disease. Several unique features of experimental autoimmune encephalomyelitis in marmosets, together with their outbred nature and close genetic and immunologic similarities to humans, create an attractive experimental model for translational research into MS, particularly for the preclinical evaluation of new biologic therapeutic molecules that cannot be investigated in rodents because of their species specificity. Moreover, this model provides new insights into possible pathogenetic mechanisms in MS.