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Abstract
BackgroundExperimental autoimmune encephalomyelitis (EAE) in the common marmoset monkey (Callithrix jacchus) is a relevant preclinical model for translational research into immunopathogenic mechanisms operating in multiple sclerosis (MS). Prior studies showed a core pathogenic role of T and B cells specific for myelin oligodendrocyte glycoprotein (MOG). However, in those studies, the quality of the response against MOG epitopes was strongly biased by bacterial antigens in the complete Freund’s adjuvant (CFA), in which the immunizing recombinant human (rh) MOG protein had been formulated. In response to the need of a more refined EAE model, we have tested whether disease could also be induced with rhMOG in incomplete Freund’s adjuvant (IFA).MethodMarmosets were immunized with rhMOG emulsified in IFA in the dorsal skin. Monkeys that did not develop neurological deficit were given booster immunizations at 28-day interval with the same antigen preparation. In a second experiment, three marmoset twin pairs were sensitized against MOG peptides in IFA to study a possibility for suppressive activity towards pathogenic T cells directed against the encephalitogenic epitope MOG40-48.ResultsDespite the absence of strong danger signals in the rhMOG/IFA inoculum, all monkeys developed clinically evident EAE symptoms. Moreover, in all monkeys, demyelinated lesions were present in the white matter and in two cases also in the cortical grey matter. Immune profiling at height of the disease showed a dominant T cell response against the overlapping peptides 14–36 and 24–46, but reactivity against the pathogenically most relevant peptide 34–56 was conspicuously absent. In the second experiment, there was an indication for a possible suppressive mechanism.ConclusionsImmunization of marmoset monkeys with rhMOG in IFA elicits clinical EAE in all animals. Moreover, rhMOG contains pathogenic and regulatory epitopes, but the pathogenic hierarchy of rhMOG epitopes is strongly influenced by the adjuvant in which the protein is formulated.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0378-5) contains supplementary material, which is available to authorized users.
Highlights
Experimental autoimmune encephalomyelitis (EAE) in the common marmoset monkey (Callithrix jacchus) is a relevant preclinical model for translational research into immunopathogenic mechanisms operating in multiple sclerosis (MS)
RhMOG contains pathogenic and regulatory epitopes, but the pathogenic hierarchy of recombinant human MOG (rhMOG) epitopes is strongly influenced by the adjuvant in which the protein is formulated
We discovered that full clinical development of EAE involves transition to a previously unknown pathogenic mechanism, mediated by MHC class I/CajaE-restricted effector memory cytotoxic T cells (CTL) specific for the epitope MOG40-48 [9]
Summary
In contrast to IL-17A and IFN-γ production, production of the pro-inflammatory cytokine TNFα was found increased in all three organs, especially in the spleen These data suggest that immunization with rhMOG in IFA may induce a Th1 prone cytokine profile, which is consistent with the dominant proliferative response of T cells against the peptides MOG14-36/. Antibody responses in the linked and unlinked epitope immunized monkeys Sera collected at periodic intervals were tested for binding to ELISA plates coated with rhMOG or MOG peptides. IgM and IgG antibody levels against MOG20-50 and rhMOG showed exactly the same patterns as against MOG24-56, and no positive signal was measured against the B cell epitope MOG54-76 (data not shown).
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