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 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-gamma, TNF, and IL-1alphabeta 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.
Pagenstecher
A
A
Departments of Neuropharmacology and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Lassmann
S
S
Carson
M J
MJ
Kincaid
C L
CL
Stalder
A K
AK
Campbell
I L
IL
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D018390:Gene Targeting; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D007111:Immunity, Cellular / Q000235:genetics*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012313:RNA / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology; D019076:Transgenes / Q000276:immunology
D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D015815:Cell Adhesion Molecules; D005904:Glial Fibrillary Acidic Protein; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D018664:Interleukin-12; D012313:RNA; D007371:Interferon-gamma