Curing CNS autoimmune disease with myelin‐reactive Foxp3<sup>+</sup> Treg

Stephens, Leigh A.; Malpass, Katy; Anderton, Stephen M.

doi:10.1002/eji.200839073

Cited by 174 publications

(134 citation statements)

References 51 publications

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“…T reg cells play an important protective role in EAE based on the finding that mice depleted of T reg cells exhibit increased susceptibility to EAE, whereas adoptive transfer of T reg cells reduced EAE incidence (Akirav et al 2009;Bebo et al 2009;Stephens et al 2009). IL-10 was reported as a factor provided by T H 2 cells that prevents T H 1 cytokine production.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…Recently, Tregs have also been investigated in clinical trials to prevent/treat T1D, graft-versushost diseases, and organ transplant rejection (16). Notably, it is well established in several models that Ag-specific Tregs are more effective than polyclonal Tregs in immunosuppression in vitro and control of autoimmunity in vivo (e.g., T1D, arthritis, multiple sclerosis, arthritis, colitis) (17)(18)(19)(20)(21)(22)(23)(24); particularly, injection of small numbers of Ag-specific Tregs selectively expanded in vitro can reverse diabetes even after disease onset (17,18). However, whether Ag-specific Tregs can be expanded in vivo, whether these cells retain their immunosuppressive function following expansion, and the stability of their Foxp3 expression have not yet been elucidated.…”

mentioning

confidence: 99%

Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Manirarora

Wei

2015

The Journal of Immunology

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Regulatory T cells (Treg) play a crucial role in the maintenance of self-tolerance. In this study, we sought to expand Ag-specific Tregs in vivo and investigate whether the expanded Tregs can prevent or delay the development of type 1 diabetes (T1D) in the NOD mouse model. NOD mice were treated with a combination of IL-2/anti–IL-2 Ab complex, islet Ag peptide, and rapamycin. After the combined treatment, CD4+CD25+Foxp3+ Tregs were significantly expanded in vivo, they expressed classical Treg markers, exerted enhanced suppressive functions in vitro, and protected against spontaneous development of T1D in NOD mice. Moreover, treated mice were almost completely protected from the adoptively transferred, aggressive form of T1D caused by in vitro–activated cytotoxic islet Ag-specific CD8 T cells. Protection from T1D was transferrable by Tregs and could be attributed to reduced islet infiltration of immune cells as well as the skewing of the immune response toward a Th2 cytokine profile. This new method of peripheral immune regulation could potentially contribute to development of novel immunotherapeutic strategies to prevent the development of T1D or to promote tolerance to islet transplants without using immunosuppressive drugs for long terms.

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“…In contrast with these effector T cell subsets, regulatory T cells (Tregs) have been implicated in the prevention and resolution of EAE. Increasing the number of Tregs has shown beneficial effects on EAE pathology, whereas decreasing Treg numbers worsened disease outcome (10)(11)(12)(13). It thus appears that the balance between different T cell subsets, in particular, Th1, Th17, Th2, and Tregs, may be dictating disease outcome after immunization with myelin-derived peptides.…”

mentioning

confidence: 99%

Coronin 1-Mediated Naive T Cell Survival Is Essential for the Development of Autoimmune Encephalomyelitis

Siegmund

Zeis

Kunz

et al. 2011

The Journal of Immunology

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Autoimmune encephalomyelitis is a disease of the CNS that can develop when an initial peripheral inflammatory stimulus is followed by infiltration and reactivation of T lymphocytes in the CNS. We report a crucial role for coronin 1, which is essential for maintenance of the naive T cell pool, for the development of murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In the absence of coronin 1, immunization with myelin oligoglycoprotein (MOG35–55) peptide largely failed to induce EAE symptoms, despite normal mobilization of leukocyte subsets in the blood, as well as effector cytokine expression comparable with wild-type T cells on polyclonal stimulation. Susceptibility of coronin 1-deficient mice to EAE induction was restored by transfer of wild-type CD4+ T cells, suggesting that the observed resistance of coronin 1-deficient mice to EAE development is T cell intrinsic. Importantly, although coronin 1-deficient regulatory T cells (Tregs) showed a suppressor activity comparable with wild-type Tregs, Treg depletion failed to restore EAE development in coronin 1-deficient animals. These results suggest a hitherto unrecognized role of naive T cells in the development of autoimmune encephalomyelitis and reveal coronin 1 as a crucial modulator of EAE induction.

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Curing CNS autoimmune disease with myelin‐reactive Foxp3⁺ Treg

Abstract: The potential use of CD4

Cited by 174 publications

References 51 publications

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Coronin 1-Mediated Naive T Cell Survival Is Essential for the Development of Autoimmune Encephalomyelitis

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Curing CNS autoimmune disease with myelin‐reactive Foxp3+ Treg

Abstract: The potential use of CD4

Cited by 174 publications

References 51 publications

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Coronin 1-Mediated Naive T Cell Survival Is Essential for the Development of Autoimmune Encephalomyelitis

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Curing CNS autoimmune disease with myelin‐reactive Foxp3⁺ Treg