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-Deficient Heterozygous Mice Develop an Exacerbated Neural Antigen-Induced Th1 Response and Experimental Allergic Encephalomyelitis 1
* Departments of Neurology and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212; and
Gene Expression Laboratory, The Salk Institute, La Jolla, CA 92037
Peroxisome proliferator-activated receptor-
(PPAR) is a nuclear receptor transcription factor that regulates cell growth, differentiation, and homeostasis. PPAR agonists are potent therapeutic agents for type 2 diabetes, obesity, and inflammation. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis. We have shown recently that PPAR agonists inhibit EAE by blocking IL-12 production, IL-12 signaling, and neural Ag-induced Th1 differentiation. In this study, we show that the PPAR-deficient heterozygous mice develop an exacerbated EAE with prolonged clinical symptoms than the wild-type littermates, following immunization with myelin oligodendrocyte glycoprotein (MOG) p35–55 peptide. The exacerbation of EAE in PPAR+/- mice associates with an increased expansion of CD4+ and CD8+ T cells and expression of CD40 and MHC class II molecules in response to MOGp35–55 Ag. The PPAR+/- mice also showed an increase in T cell proliferation and Th1 response to MOGp35–55 Ag than the wild-type littermates. These findings suggest that PPAR be a critical physiological regulator of CNS inflammation and demyelination in EAE and perhaps multiple sclerosis and other Th1 cell-mediated autoimmune diseases.
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