The role of regulatory T cells in multiple sclerosis

Zozulya, Alla L.; Wiendl, Heinz

doi:10.1038/ncpneuro0832

Cited by 209 publications

(179 citation statements)

References 107 publications

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“…Reports on the accumulation of Treg within the murine CNS during EAE [3] and on containment of EAE relapses by CNS Treg [10,11] 15: p. 72) described the detection of low numbers of Treg in the CNS and in accordance with an earlier study elevated cell numbers in the cerebrospinal fluid of patients with MS [13]. Since increasing evidence supports an antiinflammatory role for Treg at parenchymal sites of inflammation [14], one could speculate that the repeatedly reported impairment in antiproliferative capacity of Treg found in patients with MS [15,16] is just one expression of a more thorough Treg dysfunction. Whether Treg migration to sites of active inflammation in the CNS of patients with MS is impaired has been elusive so far.…”

Section: Foxp3mentioning

confidence: 48%

“…Under conditions of experimental autoimmune neuroinflammation as in EAE, Treg accumulate in the murine CNS [4,10], most notably in the remission phases [11], counterbalancing encephalitogenic CNS responses. As mentioned above, data on the presence and function of Treg in the human CNS are sparse [12][13][14]18]. To translate our findings into human pathophysiology, we used an in vitro model of the human BBB to mimic lymphocyte diapedesis in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, data on the presence and function of Treg in the human CNS are sparse [12][13][14]18]. To translate our findings into human pathophysiology, we used an in vitro model of the human BBB to mimic lymphocyte diapedesis in vivo.…”

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confidence: 99%

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Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

et al. 2010

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Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD41 Foxp31 regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.Key words: Blood-brain barrier . Brain microvascular endothelial cells . Migration . MS . Regulatory T cells Supporting Information available online IntroductionNaturally occurring CD4 1 Foxp3 1 regulatory T cells (Treg) are essential mediators of peripheral immune tolerance, regulating inflammation in the context of infection, autoimmunity, neoplasia and transplant rejection [1]. In addition to balancing immunity within lymphoid tissues, Treg enter non-lymphoid target sites of inflammation, exerting their anti-inflammatory function there [2][3][4][5]. First, regulatory as well as effector T-cell subsets have to undergo a non-lymphoid homing receptor switch after entering secondary lymphoid tissue [6]. Upon encountering specific antigens provided by dendritic cells in the T-cell area [7], the lymphocytes acquire an activated phenotype, expressing distinct surface markers of non-lymphoid homing Ã These authors contributed equally to this work. We here combined various murine and human models quantifying transmigratory capacity and locomotion to determine how constitutive, innate Treg motility translates into diapedesis across CNS endothelium. Results Murine Treg exhibit enhanced migratory capacity in vitro and in vivoWe first characterized lymph node-derived regulatory and nonregulatory T-cell subsets with regard to their expression of surface markers indicative for adhesion, migration and activation. In line with previous results for CCR6 [17], murine Treg consistently showed a significantly higher expression for all inspected markers apart from CCR7, where the higher expression was not significant (p 5 0.126), and a significantly lower e...

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Section: Foxp3mentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

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Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

et al. 2010

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“…T H 2/T reg cellrelated cytokines like IL-4, IL-10, and TGF-b have been shown to be associated with reductions in inflammation and improvement of symptoms in MS patients (Oreja-Guevara et al 2012;Koutrolos et al 2014). In addition, these cells play a protective role in autoimmune diseases (Hedegaard et al 2008, Zozulya & Wiendl 2008. The association between inflammatory cytokines with disease activity has led to suggestions that different T-cell subsets may be involved in induction of remission/suppression of disease processes (Miller et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

Haghmorad

Salehipour

Nosratabadi

et al. 2016

Journal of Immunotoxicology

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Estrogen is a neuro-protective hormone in various central nervous system (CNS) disorders. The present study evaluated the role of estrogen during experimental autoimmune encephalomyelitis (EAE) at doses selected to mimic any suppressive potential from the hormone during pregnancy. Here, mice were ovariectomized and then 2 weeks later treated with MOG antigen to induce EAE. Concurrently, mice then received (subcutaneously) an implanted pellet to deliver varying estrogen amounts over a 21-day period. Clinical scores and other parameters were monitored daily for the 21 days. At the end of the period, brain/spinal cord histology was performed to measure lymphocyte infiltration; T-cell profiles were determined through ELISA, flow cytometry, and real-time PCR. Transcription factor expression levels in the CNS were assessed using real-time PCR; T-cell differentiation was evaluated via flow cytometry. The results demonstrated that estrogen inhibited development of EAE. Histological studies revealed limited leukocyte infiltration into the CNS. High and medium dose of estrogen increased T H 2 and T reg cell production of interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-b, but concurrently resulted in a significant reduction in production of interferon (IFN)-c, IL-17, and IL-6. Flow cytometry revealed there were also significant decreases in the percentages of T H 1 and T H 17 cells, as well as significant increase in percentages of T reg and T H 2 cells in the spleen and lymph nodes. Real-time PCR results indicated that high-and medium-dose estrogen treatments reduced T-bet and ROR-ct factor expression, but enhanced Foxp3 and GATA3 expression. Collectively, these results demonstrated that a medium dose of estrogen -similar to a pregnancy level of estrogen -could potentially reduce the incidence and severity of autoimmune EAE and possibly other autoimmune pathologies.ARTICLE HISTORY

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“…Maintenance of peripheral tolerance has been correlated with amplified TREG cells and protects against EAE progression. TREG cells are classified based on the cytokine secreted and surface phenotype (Zozulya et al, 2008 (Zozulya, Wiendl et al, 2008). Impairment of CD4 + CH25 + TREG cells transforms the thymus's efficiency in eliminating self-reactive T-cells.…”

Section: Role Of Regulatory T Cells In Multiple Sclerosismentioning

confidence: 99%

Review: A Novel Multiple Sclerosis Model Utilizing Cuprizone and Rapamycin

Bahri

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Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system leading to debilitating long-term neurologic damage, primarily due to axonal loss following unsuccessful remyelination and the limited ability to remyelinate in the adult human brain. This review summarizes the current knowledge regarding combined administration of Cuprizone (CPZ) and rapamycin as a novel animal model for MS. Utilization of CPZ induces non-immune mediated demyelination, therefore bypassing complexities of the immune system and allowing analysis of de-/remyelination. Furthermore, remyelination occurs simultaneously with demyelination due to ongoing oligodendrocyte progenitor cell (OPC) differentiation into mature oligodendrocytes (OLGs).The immunosuppressive agent, rapamycin inhibits the regulatory pathway Akt/mTOR, which primarily controls myelination. This inhibition prevents ongoing OPCs from differentiating into mature oligodendrocytes (OLGs), therefore preventing myelination. The dual CPZ/rapamycin model produces more complete demyelination and a slowed remyelination phase. The long-term relevance of this review is to assess distinct stages and contributors of de-/remyelination in MS to better assess possible therapeutics for patients diagnosed with demyelinating diseases, such as MS.

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The role of regulatory T cells in multiple sclerosis

Cited by 209 publications

References 107 publications

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

Review: A Novel Multiple Sclerosis Model Utilizing Cuprizone and Rapamycin

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