title: Transfer of severe experimental autoimmune encephalomyelitis by IL-12- and IL-18-potentiated T cells is estrogen sensitive.
abstract: 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 (MOG(35-55)). 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-gamma, but not TNF-alpha, whereas coculture with IL-18 enhanced the secretion of TNF-alpha, but not INF-gamma. However, coculture with both IL-18 and IL-12 induced high levels of both TNF-alpha and IFN-gamma. 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-alpha and IFN-gamma 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-gamma/CCR5 and TNF-alpha/CCR4/CCR7, and that estrogen treatment, which is known to inhibit both proinflammatory cytokines, can completely ablate this aggressive form of passive EAE.
authors.affiliation: Department of Experimental Pathology, Institute for Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ito
authors.forename: Agata
authors.initials: A
authors.lastname: Matejuk
authors.forename: Corwyn
authors.initials: C
authors.lastname: Hopke
authors.forename: Heather
authors.initials: H
authors.lastname: Drought
authors.forename: Jami
authors.initials: J
authors.lastname: Dwyer
authors.forename: Alex
authors.initials: A
authors.lastname: Zamora
authors.forename: Sandhya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D019264:Adoptive Transfer / Q000379:methods*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004343:Drug Implants; D004357:Drug Synergism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000276:immunology; D011257:Pregnancy Proteins / Q000008:administration & dosage / Q000494:pharmacology; D054398:Receptors, CCR4; D019713:Receptors, CCR5 / Q000096:biosynthesis; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C515355:Ccr4 protein, mouse; C515371:Ccr7 protein, mouse; D017077:Culture Media, Conditioned; D004343:Drug Implants; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D020382:Interleukin-18; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011257:Pregnancy Proteins; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55); D018664:Interleukin-12; D004958:Estradiol; D007371:Interferon-gamma