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* Department of Experimental Pathology, Institute for Medical Sciences, Kyoto University, Kyoto, Japan;
Department of Neurology, Oregon Health and Science University, Portland, OR 97201;
Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97201;
L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland; and
¶ Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97201
The aim of this study was to evaluate the roles of IL-18 and IL-12 in potentiating the encephalitogenic activity of T cell lines specific for myelin oligodendrocyte glycoprotein (MOG35–55). MOG-specific T cells stimulated with anti-CD3 and anti-CD28 in the presence of IL-12 or IL-18 alone transferred only mild experimental autoimmune encephalomyelitis (EAE) into a low percentage of recipients. However, T cells cocultured with both cytokines transferred aggressive clinical and histological EAE into all recipients. Coculture of T cells with IL-12 enhanced the secretion of IFN-
, but not TNF-
, whereas coculture with IL-18 enhanced the secretion of TNF-, but not INF-. However, coculture with both IL-18 and IL-12 induced high levels of both TNF- and IFN-. Additionally, IL-12 selectively enhanced mRNA expression of CCR5, whereas IL-18 selectively enhanced the expression of CCR4 and CCR7, and CCR4 and CCR5 were coexpressed on the surface of T cells cocultured with IL-12 and IL-18. Finally, estrogen treatment, previously found to inhibit both TNF- and IFN- production, completely abrogated all signs of passive EAE. These data demonstrate that optimal potentiation of encephalitogenic activity can be achieved by conditioning MOG-specific T cells with the combination of IL-12 and IL-18, which, respectively, induce the secretion of IFN-/CCR5 and TNF-/CCR4/CCR7, and that estrogen treatment, which is known to inhibit both proinflammatory cytokines, can completely ablate this aggressive form of passive EAE.
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