IMMUNOREGULATORY EFFECTS OF ESTROGEN IN EAE

Project: Research project

Description

DESCRIPTION (provided by applicant): In patients with multiple sclerosis
(MS), there is a distinct gender bias, with approximately twice as many
affected females as males. Sex hormones may contribute to susceptibility or
resistance to MS by influencing development and function of potentially
pathogenic T cells specific for central nervous system (CNS) antigens, as well
as regulatory T cells that might modify the course of disease. Previously, we
reported that low doses of 17beta-estradiol (E2) can reduce severity of EAE by
inhibiting activation, cytokine and chemokine production, and
encephalitogenicity of murine T cells specific for myelin oligodendrocyte
glycoprotein (MOG), proteolipid protein (PLP), or myelin basic protein (MBP),
and by inhibiting I recruitment of inflammatory cells into the CNS. Of
particular importance, estrogen treatment profoundly reduced intracellular
production of TNF-alpha, known as a critical inflammatory cytokine in EAE and
MS. Recent evaluation of E2 effects on EAE using microarray analysis of
splenocyte gene expression confirmed potent inhibition of TNF-alpha, and
further identified several previously unsuspected immune-associated candidate
genes appearing to be strongly affected by E2 treatment in vivo. These
modulatory effects of estrogen on pathogenic, recruited, and regulatory cells
in EAE are likely mediated y direct interaction with estrogen receptors (ER),
which include the classical ER-alpha and ER-beta that are internal f receptors
(iER), and possibly membrane ERs (mER) that may be distinct from iERs. This
proposal will test the hypothesis that modulation of EAE by estrogen involves
receptor-mediated regulation of TNF-alpha and several other novel immunerelated
genes, thereby inhibiting inflammatory effects of macrophages,
dendritic cells and T cells and enhancing regulatory NKT cell activity. Our
primary goals are to determine if the inhibitory effects of E2 on EAE can be
observed in spontaneous EAE in the absence of regulatory T and NKT cells, and
if inhibitory effects of E2 on EAE are mediated through iER-alpha and /or iERbeta,
or in contrast, by neither of the classical iERs. Using newly developed
ER-alpha and ER-beta knockout mice we will for the first time associate E2-
dependent regulation with either or both iERs, or alternatively with mER if E2
effects persist in double KO mice. Moreover, for each novel E2-affected gene
implicated from the microarray analysis, we will investigate the cellular
source, effects of E2 on transcription and protein production, and
contribution to EAE induction in vivo. Genes found to be important in EAE
will be further evaluated in blood cells from women with different levels of
E2. The work proposed will identify key estrogen-sensitive genes, including TNFalpha, contributing to EAE induction and resistance. Changes in these genes
can be followed during estrogen treatment as surrogate markers to verify
effective doses of estrogen. From this research, we will develop a solid
basis for using estrogen replacement therapy for MS.
StatusFinished
Effective start/end date8/15/025/31/11

Funding

  • National Institutes of Health: $334,366.00
  • National Institutes of Health: $285,369.00
  • National Institutes of Health: $340,953.00
  • National Institutes of Health: $324,628.00
  • National Institutes of Health: $247,479.00
  • National Institutes of Health: $315,132.00
  • National Institutes of Health: $272,363.00
  • National Institutes of Health: $315,174.00
  • National Institutes of Health: $259,736.00

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Estrogens
Autoimmune Experimental Encephalomyelitis
Regulatory T-Lymphocytes
Multiple Sclerosis
Dendritic Cells
Tumor Necrosis Factor-alpha
Ethinyl Estradiol
T-Lymphocytes
Estrogen Receptor beta
Natural Killer T-Cells
Microarray Analysis
Cytokines
Knockout Mice
Therapeutic Uses
Central Nervous System
Myelin Proteolipid Protein
Estradiol
Therapeutics
Macrophages
Sexism

ASJC

  • Medicine(all)
  • Neuroscience(all)