Abstract
T helper (Th)2 cells have been proposed to play a neuroprotective role in multiple sclerosis (MS). This is mainly based on “loss-of-function” studies in an animal model for MS, experimental autoimmune encephalomyelitis (EAE), using blocking antibodies against Th2 related cytokines, and knockout mice lacking Th2-related molecules. We tested whether an increase of Th2 responses (“gain-of-function” approach) could alter EAE, the approach of novel GATA binding protein 3 (GATA3)-transgenic (tg) mice that overexpress GATA3, a transcription factor required for Th2 differentiation. In EAE induced with myelin oligodendrocyte glycoprotein (MOG)35–55 peptide, GATA3-tg mice had a significantly delayed onset of disease and a less severe maximum clinical score, compared with wild-type C57BL/6 mice. Histologically, GATA3-tg mice had decreased levels of meningitis and demyelination in the spinal cord, and anti-inflammatory cytokine profiles immunologically, however both groups developed similar levels of MOG-specific lymphoproliferative responses. During the early stage, we detected higher levels of interleukin (IL)-4 and IL-10, with MOG and mitogen stimulation of regional lymph node cells in GATA3-tg mice. During the late stage, only mitogen stimulation induced higher IL-4 and lower interferon-γ and IL-17 production in GATA3-tg mice. These results suggest that a preexisting bias toward a Th2 immune response may reduce the severity of inflammatory demyelinating diseases, including MS.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS)
myelin oligodendrocyte glycoprotein (MOG)-sensitized GATA binding protein 3 (GATA3)-tg mice developed only mild tail or hind limb paresis, which was followed by remission by one month p.i
Using GATA3-tg mice, we demonstrated that a genetic background biased toward a Th2 immune response reduced Th17 immune responses by producing IFN-γ (Th1)/Th17-mediated inflammatory demyelinating disease
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). In previous EAE experiments, the role of Th2 cells has generally been investigated by using gene knockout mice or blockade of Th2 cytokines by antibodies directed against Th2 cytokines and related molecules (“loss-of-function” approach) [17,18] These “loss-of-function” studies were informative, it is unclear whether a differential increase (bias) in Th2 cells affects the susceptibility and/or the clinical course of EAE. GATA3-tg mice developed exacerbated allergen-induced airway inflammation and airway remodeling [37,38], as well as bleomycin-induced pulmonary fibrosis [30], while GATA3-tg mice had less severe autoimmune glomerulonephritis [36] This novel transgenic mouse strain has never been used for CNS autoimmune diseases, including animal models for MS. Th2 immune response may reduce the severity of autoimmune demyelinating diseases, including MS
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