ESC-derived thymic epithelial cells expressing MOG prevents EAE by central and peripheral tolerance mechanisms

Su, Min; Lin, Yujun; Cui, Cheng; Tian, Xiaohong; Lü, Xiuling; He, Zhisong; Lai, Laijun

doi:10.1016/j.cellimm.2017.10.007

Cited by 10 publications

(6 citation statements)

References 30 publications

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“…It is well-known that TECs, especially medullary TECs (mTECs), are involved in the deletion of autoreactive T cells. We have demonstrated that transplantation of ESC-TEPs expressing disease-causative self-antigen results in the deletion of the antigen-specific autoreactive T cells (47,48). Our hypothesis further proposes that transplantation of APP gene-deleted ESC-TEPs would lead to the generation of Aβ-specific autoreactive T cells that could help the production of other Aβ-specific immune cells to clear the Aβ plaques in the CNS.…”

Section: Introductionmentioning

confidence: 69%

Administration of Amyloid Precursor Protein Gene Deleted Mouse ESC-Derived Thymic Epithelial Progenitors Attenuates Alzheimer's Pathology

Zhao

Lin

et al. 2020

Front. Immunol.

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Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia in older adults. Although amyloid-beta (Aβ) plaque deposition and chronic neuroinflammation in the central nervous system (CNS) contribute to AD pathology, neither Aβ plaque removal nor anti-inflammatory therapy has shown much clinical success, suggesting that the combinational therapies for the disease-causative factors may be needed for amelioration. Recent data also suggest that systemic immunity in AD should be boosted, rather than suppressed, to drive an immune-dependent cascade needed for Aβ clearance and brain repair. Thymic epithelial cells (TECs) not only play a critical role in supporting T cell development but also mediate the deletion of autoreactive T cells by expressing autoantigens. We have reported that embryonic stem cells (ESCs) can be selectively induced to differentiate into thymic epithelial progenitors (TEPs) in vitro that further develop into TECs in vivo to support T cell development. We show here that transplantation of mouse ESC (mESC)-TEPs into AD mice reduced cerebral Aβ plaque load and improved cognitive performance, in correlation with an increased number of T cells, enhanced choroid plexus (CP) gateway activity, and increased number of macrophages in the brain. Furthermore, transplantation of the amyloid precursor protein (APP) gene deleted mESC-TEPs (APP −/−) results in more effective reduction of AD pathology as compared to wild-type (APP +/+) mESC-TEPs. This is associated with the generation of Aβ-specific T cells, which leads to an increase of anti-Aβ antibody (Ab)-producing B cells in the spleen and enhanced levels of anti-Aβ antibodies in the serum, as well as an increase of Aβ phagocytosing macrophages in the CNS. Our results suggest that transplantation of APP −/− human ESC-or induced pluripotent stem cell (iPSC)-derived TEPs may provide a new tool to mitigate AD in patients.

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Section: Introductionmentioning

confidence: 69%

Administration of Amyloid Precursor Protein Gene Deleted Mouse ESC-Derived Thymic Epithelial Progenitors Attenuates Alzheimer's Pathology

Zhao

Lin

et al. 2020

Front. Immunol.

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“…In the EAE model, it was shown that thymic epithelial expression of proteolipid protein (PLP) contributes to T-cell tolerance to PLP ( 16 ). Furthermore, the intrathymic administration of myelin oligodendrocyte glycoprotein (MOG)-expressing thymic epithelial progenitors induced specific tolerance against this antigen and significantly reduced EAE severity ( 17 , 18 ).…”

Section: Introductionmentioning

confidence: 99%

Immune Thymic Profile of the MOG-Induced Experimental Autoimmune Encephalomyelitis Mouse Model

et al. 2018

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Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease that affects the neurons of the central nervous system. Activated T cells, specific for myelin epitopes, cross the brain barriers, and react against the myelin sheath, leading to demyelination. Since T cells are generated within the thymus, here we explored, in mice, the alterations occurring in this organ throughout the different phases of the disease. We induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 females and sacrifice them at the onset (day 16) and chronic phases of disease (day 23), along with non-induced controls. We observed thymic atrophy in EAE mice at the onset that remained until the chronic phase of disease. This atrophy was associated with a preferential loss of the CD4+CD8+ double positive thymocytes, an intermediate population between the more immature CD4−CD8− double negative and the most mature single positive thymocytes. This was accompanied by an increase in the thymic medullary/cortical ratio and by an altered expression levels of genes important for T cell survival. During the chronic phase, the thymi remained atrophic, but reacquired the normal proportion of the main four thymocyte populations and the normal medullary/cortical ratio. Importantly, at the onset phase, and accompanying these thymic alterations, EAE animals presented an increased percentage of demyelinating lesion area in the cerebellum, and an increased expression of interferon gamma (Ifng), interleukin (Il) 12a, and Il17a. This study suggests dynamic thymic alterations occurring in response to EAE, from the induction to the chronic phase, that might help to elucidate the MS pathophysiology.

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“…Importantly, this approach can be combined with genetic manipulation of grafted autologous TEPs to ensure that their TEC progeny expresses desired or putative autoantigens and can thus limit thymic escape of potentially pathogenic T cells by fostering their clonal deletion or differentiation into antigen-specific tolerogenic tT reg cells. The potential efficacy of this strategy for CNS autoimmune diseases is supported by a proof-of-concept study in a preclinical model, in which transplantation of embryonic stem cell–derived TEPs engineered to express MOG rendered mice resistant to later EAE induction through deletion of MOG-autoreactive T cells and generation of MOG-specific T reg cells [ 240 ].…”

Section: Therapeutic Implications and Future Directionsmentioning

confidence: 99%

The contribution of thymic tolerance to central nervous system autoimmunity

Alberti

Handel

2020

Semin Immunopathol

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Autoimmune diseases of the central nervous system (CNS) are associated with high levels of morbidity and economic cost. Research efforts have previously focused on the contribution of the peripheral adaptive and innate immune systems to CNS autoimmunity. However, a failure of thymic negative selection is a necessary step in CNS-reactive T cells escaping into the periphery. Even with defective thymic or peripheral tolerance, the development of CNS inflammation is rare. The reasons underlying this are currently poorly understood. In this review, we examine evidence implicating thymic selection in the pathogenesis of CNS autoimmunity. Animal models suggest that thymic negative selection is an important factor in determining susceptibility to and severity of CNS inflammation. There are indirect clinical data that suggest thymic function is also important in human CNS autoimmune diseases. Specifically, the association between thymoma and paraneoplastic encephalitis and changes in T cell receptor excision circles in multiple sclerosis implicate thymic tolerance in these diseases. We identify potential associations between CNS autoimmunity susceptibility factors and thymic tolerance. The therapeutic manipulation of thymopoiesis has the potential to open up new treatment modalities, but a better understanding of thymic tolerance in CNS autoimmunity is required before this can be realised.

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ESC-derived thymic epithelial cells expressing MOG prevents EAE by central and peripheral tolerance mechanisms

Cited by 10 publications

References 30 publications

Administration of Amyloid Precursor Protein Gene Deleted Mouse ESC-Derived Thymic Epithelial Progenitors Attenuates Alzheimer's Pathology

Administration of Amyloid Precursor Protein Gene Deleted Mouse ESC-Derived Thymic Epithelial Progenitors Attenuates Alzheimer's Pathology

Immune Thymic Profile of the MOG-Induced Experimental Autoimmune Encephalomyelitis Mouse Model

The contribution of thymic tolerance to central nervous system autoimmunity

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