Astrocyte-targeted expression of IL-12 induces active cellular immune responses in the central nervous system and modulates experimental allergic encephalomyelitis

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 pf) genes, developed neurologic disease which correlated with the levels and sites of transgene-encoded IL-12 expression. Tn 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,vas also evident with marked cerebral expression of the IFN-gamma, TNF,and IL-1 alpha beta genes. Concomitant with leukocyte infiltration, the CNS expression of immune accessory molecules was induced or up-regulated, including ICAM-1, VCAM-1, and MBC class LI 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 pot activity in experimental autoimmune encephalomyelitis.