Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells

Haghmorad, Dariush; Amini, Abbas; Mahmoudi, Mohammad; Rastin, Maryam; Hosseini, Mahmoud; Mahmoudi, Mahmoud

doi:10.1016/j.jneuroim.2014.10.004

Cited by 56 publications

(38 citation statements)

References 49 publications

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“…Since MS is often considered to be a T-cellmediated autoimmune disease, the initial focus of immunomodulatory roles for estrogen was on T-cells (Bodhankar et al 2011). Recently, we demonstrated that treatment of EAE with pregnancy levels of estrogen invariably reduced subsequent neurologic disease, in part, through a suppression of T H 1 and T H 17 cell functions and a shift toward T H 2 and T reg cells (Haghmorad et al 2014a). Polanczyk et al (2004) demonstrated that protective effects of estrogen treatment were not mediated through direct action on the encephalitogenic T-cells, and that both immune and CNS cells were required in propagating immunomodulatory effects of E2.…”

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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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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“…Animals were weighed and then observed for clinical symptoms in a blinded manner. Disease severity of the induced EAE was performed according to a standard scale: 0 ¼ no symptoms; 1 ¼ partial loss of tail tonicity; 2 ¼ complete loss of tail tonicity; 3 ¼ flaccid tail and abnormal gait; 4 ¼ hind leg paralysis; 5 ¼ hind leg paralysis with hind body paresis; 6 ¼ hind and foreleg paralysis; and 7 ¼ death (Haghmorad et al 2014). …”

Section: Eae Inductionmentioning

confidence: 99%

St. John’s wort and its component hyperforin alleviate experimental autoimmune encephalomyelitis through expansion of regulatory T-cells

Nosratabadi

Rastin

Sankian

et al. 2015

Journal of Immunotoxicology

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Multiple sclerosis (MS) is a central nervous system disorder mainly characterized by inflammation, demyelination and axonal injury. Anti-inflammatory agents can be used to ameliorate the disease process. Hypericum perforatum L or St. John's wort is widely used as an anti-depressant and antiinflammatory remedy in traditional and herbal medicine. Based on St. John's wort properties, the therapeutic potentials of an H. perforatum extract (HPE) and a single component, hyperforin were evaluated for effectiveness against MOG 35-55 -induced experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. Female C57BL/6 mice were immunized with specific antigen MOG 35-55 and then administered different doses of hyperforin or HPE postimmunization. Clinical symptoms/other relevant parameters were assessed daily. Histological analysis of the spinal cord was performed. T-cell proliferative activity was also evaluated using a BrdU assay. The effect of hyperforin on regulatory T-cells (T reg cells) was assessed using flow cytometry. The results indicate hyperforin and HPE reduced the incidence and severity of EAE, an outcome that closely correlated with an inhibition of pathological features (leukocyte infiltration and demyelination) and antigen-specific T-cell proliferation. The study also showed that hyperforin caused increased T reg cell levels in the spleen. These results indicated that hyperforin and HPE could attenuate EAE autoimmune responses by inhibiting immune cell infiltration and expansion of T reg cell and could eventually be considered as a potential candidate for use in the treatment of MS. ARTICLE HISTORY

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“…Another study has confirmed suppressed production of IL-17 and TNF-α in cells from pregnant mice, compared to virgin controls with EAE [51]. Enhanced production of anti-inflammatory cytokines in splenocytes and increased percentage of Th2 and Treg cells in pregnant animals have been found by Haghmorad et al [52]. Real-time PCR for transcription factors and related cytokines of Th1, Th2, Th17, and Treg cells in the CNS of the same animals have shown reduced expression levels of Th1 and Th17 transcription factors, and decreased Th1 and Th17 cytokines including IFN-γ, TNF-α, IL-17, and IL-23.…”

Section: Influence Of Gender and Sex Hormones On Eaementioning

confidence: 53%

“…Earlier studies could not find any histopathological differences between virgin and pregnant mice with EAE [49,50], but a succeeding investigation found reduced CNS demyelination and cell infiltration during late pregnancy in animals with preinduced EAE [51]. Later on, an elegant experiment of Haghmorad et al [52] has confirmed that pregnancy-induced alleviation of clinical manifestations is accompanied by reduced CNS demyelination and cell infiltration. Important information about the mechanisms underlying the amelioration of the disease activity is provided by examinations of the immunological changes related to pregnancy.…”

Section: Influence Of Gender and Sex Hormones On Eaementioning

confidence: 98%

“…Numerous studies using rats, rabbits, guinea pigs, and SJL mice have confirmed that pregnancy reduces the incidence of the disease and/or delays the day of onset [46][47][48][49][50]. Data about clinical improvement of EAE during pregnancy are also highly consistent [42,[49][50][51][52]. Earlier studies could not find any histopathological differences between virgin and pregnant mice with EAE [49,50], but a succeeding investigation found reduced CNS demyelination and cell infiltration during late pregnancy in animals with preinduced EAE [51].…”

Section: Influence Of Gender and Sex Hormones On Eaementioning

confidence: 99%

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Sex Hormones and Multiple Sclerosis

Trenova¹

2016

Trending Topics in Multiple Sclerosis

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Experimental and clinical data about the influence of sex hormones on the course of multiple sclerosis (MS) grow rapidly during the past two decades. Estrogens, progesterone, and androgens have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in animals, and pregnancy in women is associated with a dramatic reduction in disease activity. Immunomodulatory and neuroprotective properties of sex hormones are the most probable underlying mechanisms, creating a background for testing similar hormonal treatments in humans. Several pilot studies in this field present promising results, but larger trials are necessary to identify the adverse events and to estimate precisely the place of sex steroids in multiple sclerosis therapeutic strategies.The objective of this chapter is to summarize the recent advances in the research about the effects of sex steroids in EAE and MS and to create a ground for the development of more powerful treatments in the future.

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Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells

Cited by 56 publications

References 49 publications

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

St. John’s wort and its component hyperforin alleviate experimental autoimmune encephalomyelitis through expansion of regulatory T-cells

Sex Hormones and Multiple Sclerosis

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