The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood–brain barrier disruption: Implications for multiple sclerosis treatment

Bourrié, Bernard; Bribes, Estelle; Esclangon, Martine; Garcia, Laurent; Marchand, Jean; Thomas, Corinne; Maffrand, Jean‐Pierre; Casellas, Pierre

doi:10.1073/pnas.96.22.12855

Cited by 14 publications

(10 citation statements)

References 35 publications

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“…In contrast to the CUP model, in which the BBB remains intact (A. Kondo, Nakano, & Suzuki, 1987;McMahon EJ, 2002), peripheral blood monocytes do significantly infiltrate and contribute to the demyelinating pathology in other murine models including in EAE (Ajami, et al, 2011;Bourrie et al, 1999) and following stereotactic injection of LPC (de Paula Faria et al, 2014).…”

Section: Microglia But Not Infiltrating Macrophages Are Found In Cup mentioning

confidence: 90%

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Marzan

West²,

Salzer

2018

Preprint

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Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS). The precise role of microglia during demyelination, and the relative contributions of microglia vs. peripheral macrophages, are incompletely understood. Here, using a genetic fate mapping strategy, we identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Pharmacological depletion of microglia demonstrates these cells are necessary for the demyelination, loss of oligodendrocytes, and reactive astrocytosis normally evident in this model. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these damaged myelin sheaths are lost upon-repopulation of microglia.Injection of colony-stimulating factor-1 to drive focal microgliosis in white matter is sufficient to induce focal demyelination in vivo. These studies indicate activated microglia are required for demyelination that results from primary myelin pathology and are sufficient to induce demyelination directly.Stem Cell and the NIH. DM was a recipient of an NRSA fellowship from NINDS.

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Section: Microglia But Not Infiltrating Macrophages Are Found In Cup mentioning

confidence: 90%

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Marzan

West²,

Salzer

2018

Preprint

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“…However, these effects may be considered to reduce manifestations of radiation enteropathy in the rat, rather than aggravate them as we have observed in our studies. Xaliproden reduced inflammation and the expression of tumor necrosis factor-α and interferon-γ in a rat model of autoimmune encephalomyelitis [34]. However, reduced inflammation may again be considered to reduce manifestations of radiation injury in the intestine and the heart, rather than aggravate them.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart

et al. 2013

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Radiation therapy in the treatment of cancer is dose limited by radiation injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-β1) in intestinal and cardiac radiation injury, we studied the influence of pharmacological induction of TGF-β1 with xaliproden (SR 57746A) in rat models of radiation enteropathy and radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-β induction may enhance radiation injury in heart and intestine, animals were exposed to irradiation schedules that cause mild to moderate (acute) radiation injury. In the radiation enteropathy model, male Sprague-Dawley rats received local irradiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal injury was assessed at 2 weeks and 12 weeks after irradiation. In the RIHD model, male Sprague-Dawley rats received local heart irradiation with a single dose of 18 Gy and were followed for 6 months after irradiation. Rats were treated orally with xaliproden starting 3 days before irradiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-β1 levels by 300% and significantly induced expression of TGF-β1 and TGF-β1 target genes in the irradiated intestine and heart. Various radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-β1 induction. Similarly, in the RIHD model induction of TGF-β1 augmented radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-β1 in biological mechanisms of radiation-induced adverse remodeling in the intestine and the heart.

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“…In this context, it has been shown that delivery of IL-10 within the CNS induces down-regulation of the microglia/macrophage functions (55), which are believed to play a critical role in the effector phase of EAE (56±58). In addition, the ability of the regulatory cells to enter the CNS would be facilitated by the chemokine milieu (59,60) and by the disruption of the blood±brain barrier during EAE (61,62).…”

Section: Discussionmentioning

confidence: 99%

Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin

Mañá

Goodyear²,

Bernard³

et al. 2004

International Immunology

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Multiple sclerosis (MS) is a common in¯ammatory disease of the central nervous system. Although the etiology of MS remains unknown, studies in experimental autoimmune encephalomyelitis (EAE) have suggested that foreign molecules, which show molecular mimicry with myelin antigens, may play an important role as causative agents of the human disease. In this study, we investigate the molecular mimicry between the extracellular Ig-like domain of the cow's milk protein butyrophilin (BTN) and the extracellular domain of myelin oligodendrocyte glycoprotein (MOG), a candidate autoantigen in MS. Interestingly, we found that as a result of a non-pathogenic cross-reactivity that is localized to a subdominant region of MOG, treatment of C57BL/6 mice with BTN either before or after immunization with MOG was shown to prevent and also suppress the clinical manifestations of EAE. BTN treatment resulted in a signi®cant reduction in both proliferation and production of T h 1-related cytokines (IFN-g, IL-2, IL-12 and granulocyte macrophage colony stimulating factor) in response to MOG. This speci®c inhibition was consistently associated with an up-regulation in IL-10 secretion. Furthermore, adoptive transfer of BTN-speci®c T cells prior to active immunization with MOG resulted in a transitory reduction of the clinical symptoms. Our results suggest that the clinical improvement associated with BTN treatment involved the combination of both anergy and regulatory cells secreting high levels of IL-10. In conclusion, we show that despite the traditional link between molecular mimicry and pathogenic immune response, environmental agents that share homology with autoantigens may also represent a source of cells with a protective phenotype.

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The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood–brain barrier disruption: Implications for multiple sclerosis treatment

Abstract: Experimental autoimmune encephalomyelitis (EAE) is a T cell autoimmune disorder that is

Cited by 14 publications

References 35 publications

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart

Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin

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