Dataset Information

Tolerogenic Vaccination with MOG/VitD Overcomes Aggravating Effect of C. albicans in Experimental Encephalomyelitis.

ABSTRACT: AIMS:Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS). We described that Candida albicans (Ca) aggravates experimental autoimmune encephalomyelitis (EAE) that is a model to study MS. We also observed that vaccination with a myelin peptide (MOG) in the presence of vitamin D (VitD) protected mice against EAE. In this work, we investigated whether Ca infection interferes with the efficacy of this vaccine. METHODS:EAE was induced in C57BL/6 female mice previously vaccinated with MOG+VitD and then infected 3 days before encephalomyelitis induction. RESULTS:Vaccination was able to control EAE development in infected mice. These animals gained weight, and only a few progressed to very low clinical scores. Protection was confirmed by a lower inflammatory infiltration in the CNS and was also associated with a reduced production of encephalitogenic cytokines by spleen and CNS cell cultures. The elevated percentage of CD25(+) FoxP3(+) cells suggests that regulatory T cells are involved in the protection. Adoptive transfer of splenocytes from mice vaccinated with MOG+VitD supports the view that protection is mediated by immunoregulatory cells. CONCLUSION:Together, these experiments provide evidence demonstrating that EAE can be prevented by the inverse vaccination with MOG+VitD even in the presence of a disease-aggravating infectious agent.

SUBMITTER: Fraga-Silva TF

PROVIDER: S-EPMC6492784 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tolerogenic Vaccination with MOG/VitD Overcomes Aggravating Effect of C. albicans in Experimental Encephalomyelitis.

Fraga-Silva Thais F C TF Mimura Luiza A N LA Zorzella-Pezavento Sofia F G SF Ishikawa Larissa L W LL França Thais G D TG Thomé Rodolfo R Verinaud Liana L Arruda Maria S P MS Sartori Alexandrina A

CNS neuroscience & therapeutics 20160619 10

<h4>Aims</h4>Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS). We described that Candida albicans (Ca) aggravates experimental autoimmune encephalomyelitis (EAE) that is a model to study MS. We also observed that vaccination with a myelin peptide (MOG) in the presence of vitamin D (VitD) protected mice against EAE. In this work, we investigated whether Ca infection interferes with the efficacy of this vaccine.<h4>Methods</h4>EAE was induced ...[more]

PMID: 27321391

Similar Datasets

Project description:BackgroundAlthough effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MS-associated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes.MethodsIn this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35-55-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1?,25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load.ResultsTreatment of MOG35-55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35-55-pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35-55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score.ConclusionsElectroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS.

Project description:The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-As: MOG92-106 specific transgenic T cell receptor (TCR1640) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR1640 mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR1640 mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression.

Dataset Information

Tolerogenic Vaccination with MOG/VitD Overcomes Aggravating Effect of C. albicans in Experimental Encephalomyelitis.

Publications

Tolerogenic Vaccination with MOG/VitD Overcomes Aggravating Effect of C. albicans in Experimental Encephalomyelitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets