Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis

Offner, Halina; Adlard, Kirsten; Zamora, Alex; Vandenbark, Arthur A.

doi:10.1172/jci9213

Cited by 103 publications

(98 citation statements)

References 59 publications

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“…As shown previously, treatment with17 -estradiol (E2) resulted in a delay in onset as well as decreased incidence and severity of disease (Fig. 1, Table 1) (Jansson et al 1994, Offner et al 2000, Ito et al 2001. To determine whether the protective effects of estrogen in this model were estrogen receptor-mediated, mice were treated with both E2 and the estrogen receptor antagonist ICI 182 780.…”

Section: Effect Of An Er Antagonist On Eae Induced By the Adoptive Trmentioning

confidence: 70%

“…Previous studies examining immune responses in estrogen-treated mice in the EAE model have produced variable results, demonstrating a suppression of Th1 cytokine production with or without a concomitant increase in Th2 cytokines that was associated with disease suppression (Kim et al 1999, Offner et al 2000, Ito et al 2001. Our results show that treatment with PPT is associated with a decrease of both Th1 and Th2 cytokines, suggesting that suppression of disease by ER -selective agonists may not involve immune deviation to a Th2 response, but a global suppression of PLP-specific T cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…The pregnancy hormone estriol (E3) has been shown to decrease the number and volume of lesions in the brains of relapsingremitting MS patients, as well as decrease IFN-levels in peripheral blood mononuclear cells (Sicotte et al 2002). It has also been demonstrated that estrogens can suppress disease in murine experimental autoimmune encephalomyelitis (EAE), a well-defined model for multiple sclerosis (Jansson et al 1994, Kim S et al 1999, Offner et al 2000, Ito et al 2001. As in humans, disease suppression by estrogen was associated with decreased production of pro-inflammatory/Th1 cytokines , Ito et al 2001.…”

Section: Introductionmentioning

confidence: 99%

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Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Elloso¹,

Phiel²,

Henderson³

et al. 2005

Journal of Endocrinology

100

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Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ER and ER . The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17 -estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ER -selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ER -selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ER agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ER -selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

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Section: Effect Of An Er Antagonist On Eae Induced By the Adoptive Trmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Elloso¹,

Phiel²,

Henderson³

et al. 2005

Journal of Endocrinology

100

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“…In the search for effective MS treatments, much has been invested in estrogens and ER agonists because of their neuroprotective benefits (5,10,25,26). Different ERβ ligand analogs have distinct effects on gene transcription in signaling pathways for chromosome replication, cell death, and OPC differentiation (27).…”

Section: Discussionmentioning

confidence: 99%

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis

Moore¹,

Khalaj

Kumar

et al. 2014

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

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Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) β agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.M ultiple sclerosis (MS) is an autoimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS) that affects 2-2.5 million people worldwide. Currently approved MS drugs reduce relapse rates but fail to reverse or prevent neurodegeneration and disability progression. Disease-modifying drugs capable of restoring neuronal function via axon remyelination (RM) represent a major unmet goal for MS therapeutics.Oligodendrocyte (OL) progenitor cells (OPCs) are responsible for remyelinating axons, make up at least 3% of all white matter cells, and are present in and around MS lesions; however, they remain largely quiescent in the adult CNS (1). Although endogenous RM can occur in patients with MS, as evidenced by shadow plaques, it is short-lived, incomplete, and relatively ineffective (2). Transition to progressive MS is characterized by increased axon loss, which correlates with RM failure (3). Hence, a treatment that stimulates endogenous OPCs to differentiate and remyelinate axons would reduce axon degeneration and restore neuronal function.Experimental autoimmune encephalomyelitis (EAE) affords researchers an in-depth, mechanistic understanding of immunemediated, demyelinating neurodegeneration and anti-inflammatory effects of currently approved MS drugs. Our recent work has demonstrated promising neuroprotective effects of the estrogen receptor (ER) β agonist 2,3-bis(4-hydroxyphenyl)propionitrile...

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“…Indeed, recent evidence suggests that estrogens could influence the gender difference observed in MS and other neurological disorders [17]. Studies on animal models have shown estradiol (E2) dose dependent inhibition of clinical signs of EAE when E2 was given a week before EAE induction [18] and [19]. Also of interest, several positive association results have been found between estrogen receptor variants and other autoimmune disorders including lupus and rheumatoid arthritis [20] and [21] as well as with the Parkinson neurodegenerative disease [22].…”

Section: Discussionmentioning

confidence: 99%

Allelic variation investigation of the estrogen receptor within an Australian multiple sclerosis population

Tajouri

Fernandez

Tajouri

et al. 2007

Journal of the Neurological Sciences

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Multiple Sclerosis (MS) is a central nervous system (CNS) chronic inflammatory demyelinating disease leading to various neurological disabilities. The disorder is more prevalent for women with a ratio of 3:2 female to male. Objectives: To investigate variation within the estrogen receptor 1 (ESR1) polymorphism gene in an Australian MS case-control population using two intragenic restriction fragment length polymorphisms; the G594A located in exon 8 detected with the BtgI restriction enzyme and T938C located in intron 1, detected with PvuII. One hundred and ten Australian MS patients were studied, with patients classified clinically as Relapsing Remitting MS (RR-MS), Secondary Progressive MS (SP-MS) or Primary Progressive MS (PP-MS). Also, 110 age, sex and ethnicity matched controls were investigated as a comparative group. No significant difference in the allelic distribution frequency was found between the case and control groups for the ESR1 PvuII (P = 0.50) and Btg1 (P = 0.45) marker. Our results do not support a role for these two ESR1 markers in multiple sclerosis susceptibility, however other markers within ESR1 should not be excluded for potential involvement in the disorder.

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Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis

Cited by 103 publications

References 59 publications

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis

Allelic variation investigation of the estrogen receptor within an Australian multiple sclerosis population

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