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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 (CD44high,
CD45Rblow, CD62Llow, CD69high,
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-1
ß
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.
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