From classic to spontaneous and humanized models of multiple sclerosis: Impact on understanding pathogenesis and drug development

Ben‐Nun, Avraham; Kaushansky, Nathali; Kawakami, Naoto; Krishnamoorthy, Gurumoorthy; Berer, Kerstin; Liblau, Roland; Hohlfeld, Reinhard; Wekerle, Hartmut

doi:10.1016/j.jaut.2014.06.004

Cited by 142 publications

(104 citation statements)

References 192 publications

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“…The advent of novel transgenic mouse models featuring spontaneous development of CNS inflammation offers the unique opportunity to study the very first steps in immune cell activation and lesion development (21,22). This model is in contrast to conventional EAE models, where exogenous application of microbial adjuvants is indispensable for disease induction, which is known to affect the mechanisms of (auto-) immune cell activation and BBB permeability.…”

Section: Discussionmentioning

confidence: 99%

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Klotz

Kuzmanov

Hucke

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the bloodbrain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4 + T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immuneregulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.neuroinflammation | multiple sclerosis | spontaneous EAE | CNS lesion distribution | blood-brain barrier M ultiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Disease pathogenesis is initiated by peripheral activation of autoimmune T lymphocytes by yet unknown mechanisms, followed by T-cell expansion and subsequent migration across the complex structure of the blood-brain barrier (BBB). Within the CNS, entry of this first wave of T cells elicits recruitment of other immune cells, which together evoke a local inflammatory process ultimately resulting in demyelination, as well as axonal and neuronal damage (1). Several histological MS subtypes have been described with regard to lesion distribution and cellular composition (2). The reasons underlying distinct lesion development at different anatomical sites still remain however largely elusive: Some authors have proposed that the nature and expression pattern of the target autoantigen might play a role (3, 4). Others have observed an influence of the HLA complex and its role in shaping antigen presentation, thus suggesting that T-cell antigen specificity might impact the location of inflammation (5). Additionally, T-cell polarization into distinct T helper subtypes, as well as their expression pattern of chemokine receptors and adhesion molecules, has been implicated in determining the lo...

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Section: Discussionmentioning

confidence: 99%

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Klotz

Kuzmanov

Hucke

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…[1,12] A series of T-cell epitopes are well-defined for a range of CNS myelin autoantigens: [13] most notably, myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), but there are others. Therefore, EAE is an ideal model system in which the efficacy of PIT can be tested and its mechanistic basis can be probed.…”

Section: Eae As a Testing Ground For Pitmentioning

confidence: 99%

“…The availability of mouse lines bearing transgenic T-cell receptors (TCRs) that recognize individual myelin peptides has increased the level of sophistication that can be achieved in understanding the mode of action of PIT. [1,[18][19][20][21][22] Although some myelin peptide-major histocompatibility complex (MHC) tetramers are available to analyze endogenously generated responses amongst polyclonal TCR repertoires, [23][24][25] these have not been adopted broadly for these types of studies.…”

Section: Eae As a Testing Ground For Pitmentioning

confidence: 99%

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Peptide immunotherapy in experimental autoimmune encephalomyelitis

Anderton¹

2015

Biomed J

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“…Some aspects of EAE resemble the complexity of MS in humans. Hence, EAE helps to understand the immunologic mechanisms involved in the pathogenesis of MS and to test a variety of therapeutic agents [3,4].…”

Section: Introductionmentioning

confidence: 99%

Treatment with a recombinant human IgM that recognizes PSA-NCAM preserves brain pathology in MOG-induced experimental autoimmune encephalomyelitis

Lemus

Warrington

Denic

et al. 2017

HAB

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Abstract. A single peripheral dose of CNS-binding IgMs promote remyelination and preserve axons in a number of animal models of neurologic disease. A myelin-binding recombinant human IgM (rHIgM22) is presently in a safety trial in MS patients following an acute MS exacerbation. rHIgM22 (directed against oligodendrocytes) or rHIgM12 (directed against neurons) were administered to mice with MOG-induced experimental autoimmune encephalomyelitis (EAE) with study endpoints: clinical deficits and brain and spinal cord pathology. IgMs were administered at a therapeutic dose of 100 µg intra peritoneal at the time of immunization (day −1, 0, +1), disease onset (15 days) or peak of the disease (28 days). Disease course was not worsened by either human IgM regardless of the time of treatment. Of note, the human IgM that recognizes a carbohydrate epitope on gangliosides and NCAM, rHIgM12, reduced brain pathology when given at time of immunization or at onset of disease, but did not reduce clinical deficits or spinal cord disease burden. Hence, treatment with rHIgM12 resulted in marked reduction in meningeal inflammation. Data consistent with the hypothesis that in the EAE model this molecule has an immune-modulatory effect. Treatment with an anti-CD4 blocking IgG prevented both clinical course and CNS pathology. This pre-clinical study further supports the safety of therapeutic CNS-binding human IgMs in the presence of autoimmunity and clearly differentiates them from IgGs directed against MOG or aquaporin-4 that worsen neurologic disease.

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From classic to spontaneous and humanized models of multiple sclerosis: Impact on understanding pathogenesis and drug development

Cited by 142 publications

References 192 publications

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Peptide immunotherapy in experimental autoimmune encephalomyelitis

Treatment with a recombinant human IgM that recognizes PSA-NCAM preserves brain pathology in MOG-induced experimental autoimmune encephalomyelitis

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