Translational multiple sclerosis research in primates:Mind the gap

Populaire samenvattingMultiple sclerose (MS) is een chronische aandoening waarbij het afweersysteem de hersenen en het ruggenmerg aantast. De oorzaak van deze verstoorde reactie van het afweersysteem is nog onbekend. Alhoewel het aantal behandelingen voor MS groeiende is, is er nog steeds geen behandeling dat de ziekte stopt of voorkomt in alle patiënten. De ontwikkeling van nieuwe therapieën wordt, onder andere, belemmerd door het gebrek aan diermodellen die het pathogene mechanisme dat MS veroorzaakt nauwkeurig weerspiegelt. Het experimentele auto-immune encefalomyelitis (EAE) model wordt veelal gebruikt om deze pathogene mechanismen in MS te onderzoeken alsmede voor het testen van nieuwe behandelingen. Het onderzoek van promovendus Jordon Dunham werd gefinancierd vanuit een onderzoeksprogramma van Marie Skłodowska-Curie van de Europese Commissie (Neurokine). Hij heeft zijn onderzoek verricht bij de afdeling Neurowetenschappen van het UMCG en bij het Biomedical Primate Research Centre (BPRC) in Rijswijk. Het onderzoek voor zijn proefschrift had twee doelen: i) het gebruik van niet-humane primaten (NHP) modellen om een beter begrip te krijgen van de pathogene immuun-mechanismen die ten grondslag liggen aan MS en ii) te bepalen in hoeverre aap-modellen belangrijke aspecten nabootsen van de pathologie die wordt gezien in de hersenen van mensen met MS.Dit proefschrift beschrijft hoe een herpesvirus (EBV), dat erkend wordt als een belangrijke risicofactor voor MS, de functie van B- en T-lymfocyten verandert. Deze veranderingen spelen mogelijk een belangrijke rol in de pathogene mechanismen van de ziekte. Een andere belangrijke bevinding van dit proefschrift is dat de pathologie in de hersenen van klauwaapjes met MS-achtige ziekte de pathologie in MS beter nabootst dan de veelvuldig gebruikte knaagdiermodellen van de ziekte.Ten slotte, de immunologische en pathologische gelijkheid van de primaten EAE modellen ten opzichte van MS maakt deze diermodellen zeer waardevol in het translationele onderzoek naar de rol van EBV in de pathogenese van MS en voor de ontwikkeling van innovatieve behandelingen.Multiple sclerosis (MS) is a chronic disabling disease caused by an attack of the immune system on the brain and spinal cord. The cause of the inappropriate immune system activity is still unknown and although the number of therapeutics is increasing, there is still no treatment that can halt or prevent the disease in all patients. The development of new therapies is hindered by the paucity of animal models that accurately reflect the pathogenic mechanism causing MS. The experimental autoimmune encephalomyelitis (EAE) model has been widely used to investigate these pathogenic mechanisms in MS and to test new treatments. The research of the PhD student Jordon Dunham has been funded via a project from the Marie Skłodowska-Curie research fellowship program of the European Commission (Neurokine). He performed his investigations at the Neuroscience department of the UMCG and at the Biomedical Primate Research Centre (BPRC) in Rijswijk. The research for his thesis had two aims: i) to utilize non-human primate (NHP) models for gaining a better understanding of the pathogenic immune mechanisms underlying MS and ii) to determine how closely NHP models replicate key pathology features of MS. This thesis describes how a common herpes virus (EBV), which is recognized as an important environmental risk factor of MS, alters the function of B and T lymphocytes and that these changes can have an important role in the pathogenic mechanisms of disease. Another important finding of this thesis was that the pathology in the brain of marmoset monkeys with MS-like disease more closely replicates the brain pathology in MS than the more frequently used rodent models of the disease. In conclusion, the immunological and pathological proximity of primate EAE models to MS makes them valuable systems for translational research into the role of EBV in the pathogenesis of MS and for the development of innovative treatments

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.</p

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34-56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund's adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund's adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34-56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey's immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes

Enhanced axonal response of mitochondria to demyelination offers neuroprotection:implications for multiple sclerosis

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochromecoxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons,and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation.Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.</p

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34–56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund’s adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund’s adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34–56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey’s immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes

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