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Astrocyte-Targeted Expression of IL-12 Induces Active Cellular Immune Responses in the Central Nervous System and Modulates Experimental Allergic Encephalomyelitis¹

Axel Pagenstecher^2,3,*, Silke Lassmann^2,*, Monica J. Carson, Carrie L. Kincaid^*, Anna K. Stalder^* and Iain L. Campbell^4,*

Departments of ^* Neuropharmacology and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037

The role of IL-12 in the evolution of immunoinflammatory responses at a localized tissue level was investigated. Transgenic mice were developed with expression of either both the IL-12 subunits (p35 and p40) or only the IL-12 p40 subunit genes targeted to astrocytes in the mouse CNS. Glial fibrillary acidic protein (GF)-IL-12 mice, bigenic for the p35 and p40 genes, developed neurologic disease which correlated with the levels and sites of transgene-encoded IL-12 expression. In these mice, the brain contained numerous perivascular and parenchymal inflammatory lesions consisting of predominantly CD4⁺ and CD8⁺ T cells as well as NK cells. The majority of the infiltrating T cells had an activated phenotype (CD44^high, CD45Rb^low, CD62L^low, CD69^high, VLA-4 ^high, and CD25⁺). Functional activation of the cellular immune response was also evident with marked cerebral expression of the IFN-, TNF, and IL-1ß genes. Concomitant with leukocyte infiltration, the CNS expression of immune accessory molecules was induced or up-regulated, including ICAM-1, VCAM-1, and MHC class II and B7-2. Glial fibrillary acidic protein-p40 mice with expression of IL-12 p40 alone remained asymptomatic, with no inflammation evident at any age studied. The effect of local CNS production of IL-12 in the development of experimental autoimmune encephalomyelitis was studied. After immunization with myelin oligodendrocyte glycoprotein-peptides, GF-IL-12 mice had an earlier onset and higher incidence but not more severe disease. We conclude that localized expression of IL-12 by astrocytes can 1) promote the spontaneous development of activated type 1 T cell and NK cellular immunity and cytokine responses in the CNS, and 2) promote more effective Ag-specific T cell dynamics but not activity in experimental autoimmune encephalomyelitis.