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Departments of
* Neurology,
Pathology and Laboratory Medicine, and
Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Experimental autoimmune encephalomyelitis (EAE) serves as a model
for multiple sclerosis and is considered a CD4+, Th1
cell-mediated autoimmune disease. IL-12 is a heterodimeric cytokine,
composed of a p40 and a p35 subunit, which is thought to play an
important role in the development of Th1 cells and can exacerbate EAE.
We induced EAE with myelin oligodendrocyte glycoprotein (MOG) peptide
35–55 (MOG35–55) in C57BL/6 mice and found that while
IL-12p40-deficient (-/-) mice are resistant to EAE,
IL-12p35-/- mice are susceptible. Typical spinal cord
mononuclear cell infiltration and demyelination were observed in
wild-type and IL-12p35-/- mice, whereas
IL-12p40-/- mice had normal spinal cords. A Th1-type
response to MOG35–55 was observed in the draining lymph
node and the spleen of wild-type mice. A weaker
MOG35–55-specific Th1 response was observed in
IL-12p35-/- mice, with lower production of IFN-
. By
contrast, a Th2-type response to MOG35–55 correlated with
disease resistance in IL-12p40-/- mice. Production of
TNF-
by microglia, CNS-infiltrating macrophages, and
CD4+ T cells was detected in wild-type and
IL-12p35-/-, but not in IL-12p40-/-, mice.
In addition, NO production was higher in IL-12p35-/- and
wild-type mice than in IL-12p40-/- mice. These data
demonstrate a redundancy of the IL-12 system in the induction of EAE
and suggest that p40-related heterodimers, such as the recently cloned
IL-23 (p40p19), may play an important role in disease
pathogenesis.
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