IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central …

B Gran, GX Zhang, S Yu, J Li, XH Chen… - The Journal of …, 2002 - journals.aai.org
B Gran, GX Zhang, S Yu, J Li, XH Chen, ES Ventura, M Kamoun, A Rostami
The Journal of Immunology, 2002journals.aai.org
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 (MOG 35–55) in C57BL/6 mice and
found that while IL-12p40-deficient (−/−) mice are resistant to EAE, IL-12p35−/− mice are …
Abstract
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 (MOG 35–55) 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 MOG 35–55 was observed in the draining lymph node and the spleen of wild-type mice. A weaker MOG 35–55-specific Th1 response was observed in IL-12p35−/− mice, with lower production of IFN-γ. By contrast, a Th2-type response to MOG 35–55 correlated with disease resistance in IL-12p40−/− mice. Production of TNF-α 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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