Dataset Information

Accelerated course of experimental autoimmune encephalomyelitis in PD-1-deficient central nervous system myelin mutants.

ABSTRACT: It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1(-/-) mice showed an increased production of interferon-gamma by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I- or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease.

SUBMITTER: Kroner A

PROVIDER: S-EPMC2684193 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Accelerated course of experimental autoimmune encephalomyelitis in PD-1-deficient central nervous system myelin mutants.

Kroner Antje A Schwab Nicholas N Ip Chi Wang CW Ortler Sonja S Göbel Kerstin K Nave Klaus-Armin KA Mäurer Mathias M Martini Rudolf R Wiendl Heinz H

The American journal of pathology 20090514 6

It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory dise ...[more]

PMID: 19443704

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Project description:The lack of targeted and high-efficiency drug delivery to the central nervous system (CNS) nidus is the main problem in the treatment of demyelinating disease. Extracellular vesicles (EVs) possess great promise as a drug delivery vector given their advanced features. However, clinical applications are limited because of their inadequate targeting ability and the “dilution effects” after systemic administration. Neural stem cells (NSCs) supply a plentiful source of EVs on account of their extraordinary capacity for self-renewal. Here, we have developed a novel therapeutic system using EVs from modified NSCs with high expressed ligand PDGF-A (EVPs) and achieve local delivery. It has been demonstrated that EVPs greatly enhance the target capability on oligodendrocyte lineage. Moreover, EVPs are used for embedding triiodothyronine (T3), a thyroid hormone that is critical for oligodendrocyte development but has serious side effects when systemically administered. Our results demonstrated that systemic injection of EVPs + T3, versus EVPs or T3 administration individually, markedly alleviated disease development, enhanced oligodendrocyte survival, inhibited myelin damage, and promoted myelin regeneration in the lesions of experimental autoimmune encephalomyelitis mice. Taken together, our findings showed that engineered EVPs possess a remarkable CNS lesion targeting potential that offers a potent therapeutic strategy for CNS demyelinating diseases as well as neuroinflammation. Graphical abstract Schematic representation of EVPs + T3 treatment ameliorated disease development and promoted myelin regeneration.Image 1 Highlights • NSC-derived EV-PDGFA dramatically increased targeting efficiency to the lineage of OLGs and the demyelinated area in the CNS.• EVPs-T3 exert the therapeutic ability in the lesion suppressed the disease development and protected myelin loss.• EVPs-T3 increased numbers of OLGs in the lesion and TEM data evidenced that EVPs-T3 promotes myelin regeneration in vivo.

Project description:BackgroundMurine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, presents typically as ascending paralysis. However, in mice in which interferon-gamma (IFN?) signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction. This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS. However, the exact mechanism by which IFN? signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive.MethodsWe induced EAE in IFN?-/- mice and bone marrow chimeric mice in which IFN?R is not expressed in the CNS but is intact in the periphery (IFN?RCNSKO) and vice versa (IFN?RperiKO). Blood-brain barrier permeability was determined by Evans blue intravenous administration at disease onset. Populations of immune cell subsets in the periphery and the CNS were quantified by flow cytometry. CNS tissues isolated at various time points after EAE induction, were analyzed by immunohistochemistry for composition of inflammatory foci and patterns of axonal degeneration.ResultsIncidence and severity of atypical EAE were more pronounced in IFN?RCNSKO as compared to IFN?RperiKO mice. Contrary to what we anticipated, cerebella/brainstems of IFN?RCNSKO mice were only minimally infiltrated, while the same areas of IFN?RperiKO mice were extensively populated by peripheral immune cells. Furthermore, the CNS of IFN?RperiKO mice was characterized by persistent neutrophil-rich foci as compared to IFN?RCNSKO. Immunohistochemical analysis of the CNS of IFN?-/- and IFN?R chimeric mice revealed that IFN? protective actions are exerted through microglial STAT1.ConclusionsAlterations in distribution and composition of CNS inflammatory foci are not sufficient for the onset of atypical EAE. IFN? dictates the course of neuroinflammatory disorders mainly through actions exerted within the CNS. This study provides strong evidence that link microglial STAT1 inactivation to vestibular dysfunction.

Dataset Information

Accelerated course of experimental autoimmune encephalomyelitis in PD-1-deficient central nervous system myelin mutants.

Publications

Accelerated course of experimental autoimmune encephalomyelitis in PD-1-deficient central nervous system myelin mutants.

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