Treatment with 17beta-estradiol (E2) can prevent clinical and histological signs of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). E2 inhibited activation, production of cytokines (particularly TNF-alpha) and chemokines, and encephalitogenic activity of marine T cells, and prevented recruitment of inflammatory cells into the CNS. During the past granting period, we demonstrated that mice lacking Esr1 (alpha receptor for E2) but not Esr2 (beta receptor for E2) were refractory to E2-mediated inhibition of chronic EAE, thus implicating Esr7 in E2-mediated protection. Moreover, we found that E2 treatment did not directly inhibit pathogenic T cells. Transfer of E2-conditioned Esrf+ dendritic cells (DC) into Esr1 knockout mice completely suppressed EAE, indicating that DC represent at least one critical E2- sensitive cell type. Moreover, we found that E2 could up-regulate expression of FoxP3 and potentiate the regulatory activity of CD4+CD25+ Treg cells through Esr1. Of importance, E2-conditioned DC had both reduced ARC function for activating encephalitogenic T cells, and enhanced induction of CD4+CD25+FoxP3+ Treg cells. One mechanism that could account for the protective effects of E2 is its pronounced up-regulation of the PD-1 (programmed death-1) marker on DC macrophages, B cells and T cells, a finding relevant to a recently described PD-1 polymorphism associated with MS disease progression. Although our recent results have narrowed the candidates that contribute to E2 prevention of EAE, key issues still remain, including additional critical E2-sensitive cell types and the role of PD-1 in E2-induced immunoregulation. Moreover, unlike E2 that can prevent but not treat established EAE, ethinyl estradiol (EE) used in oral contraception has therapeutic effects on EAE, raising the fundamental question of whether this structurally different molecule signals through Esr1 and activates critical E2-sensitive pathways. We here propose to test the hypothesis that E2-mediated protection and EE-mediated therapy primarily involve Esr1- dependent APC and Treg cells that affect the course of EAE through enhanced PD-1 expression, reduced APC function, and heightened activity of CD4+CD25+FoxP3+ Treg cells. We thus propose to identify E2- sensitive cell types that are crucial for Esr7-mediated protection against EAE, evaluate the role of PD-1 and its ligands in the protective mechanism, and distinguish therapeutic and neuroprotective effects of EE vs. E2 in relapsing, chronic, and spontaneous models of EAE. These studies will clearly establish E2- and EE- dependent pathways of EAE protection and therapy that may have direct relevance for future clinical trials in MS patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045445-09
Application #
7846100
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Utz, Ursula
Project Start
2006-08-28
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$340,953
Indirect Cost
Name
Oregon Health and Science University
Department
Neurology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Bodhankar, Sheetal; Vandenbark, Arthur A; Offner, Halina (2012) Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17ýý-oestradiol-receptor-positive B cells that up-regulate PD-1 on CD4+ Foxp3+ regulatory T cells. Immunology 137:282-93
Bodhankar, Sheetal; Offner, Halina (2011) GPR30 FORMS AN INTEGRAL PART OF E2-PROTECTIVE PATHWAY IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. Immunol Endocr Metab Agents Med Chem 11:262-274
Bodhankar, Sheetal; Wang, Chunhe; Vandenbark, Arthur A et al. (2011) Estrogen-induced protection against experimental autoimmune encephalomyelitis is abrogated in the absence of B cells. Eur J Immunol 41:1165-75
Jones, Richard E; Kaler, Laurie; Murphy, Stephanie et al. (2010) Tissue-Dependent Expression of Estrogen Receptor ? in 17?-Estradiol-Mediated Attenuation of Autoimmune CNS Inflammation. Open Autoimmun J 2:197-204
Yates, M A; Li, Y; Chlebeck, P et al. (2010) Progesterone treatment reduces disease severity and increases IL-10 in experimental autoimmune encephalomyelitis. J Neuroimmunol 220:136-9
Subramanian, Sandhya; Ayala, Patricia; Wadsworth, Teri L et al. (2010) CCR6: a biomarker for Alzheimer's-like disease in a triple transgenic mouse model. J Alzheimers Dis 22:619-29
Wang, Chunhe; Li, Yuexin; Proctor, Thomas M et al. (2010) Down-modulation of programmed death 1 alters regulatory T cells and promotes experimental autoimmune encephalomyelitis. J Neurosci Res 88:7-15
Yates, Melissa A; Li, Yuexin; Chlebeck, Peter J et al. (2010) GPR30, but not estrogen receptor-alpha, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol. BMC Immunol 11:20
Wang, Chunhe; Dehghani, Babak; Li, Yuexin et al. (2009) Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1. J Immunol 182:3294-303
Wang, Chunhe; Dehghani, Babak; Li, Yuexin et al. (2009) Oestrogen modulates experimental autoimmune encephalomyelitis and interleukin-17 production via programmed death 1. Immunology 126:329-35

Showing the most recent 10 out of 19 publications