Functional Blocking Monoclonal Antibodies against IL-12p40 Homodimer Inhibit Adoptive Transfer of Experimental Allergic Encephalomyelitis

Abstract

IL-12p70 (p40:p35) and IL-23 (p40:p19) are bioactive cytokines and their role in experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis, are becoming clear. On the other hand, the IL-12p40 homodimer (p40(2)) was considered as an inactive or inhibitory molecule and its functions are poorly understood. To facilitate the studies on p40(2), we have recently generated neutralizing mAb against mouse p40(2). The present study demonstrates the effectiveness of p40(2) mAb in treating the disease process of relapsing-remitting EAE in female SJL/J mice. The p40(2) mAb ameliorated clinical symptoms and disease progression of EAE in recipient mice and suppressed the generation of encephalitogenic T cells in donor mice. Histological and blood-brain barrier (BBB) and blood-spinal cord barrier (BSB) permeability studies reveal that p40(2) mAb effectively inhibited the infiltration of mononuclear cells into brain and spinal cord and improved the integrity of BBB and BSB in EAE mice. Consequently, p40(2) mAb also suppressed the expression of proinflammatory molecules, normalized the expression of myelin genes, and blocked demyelination in the CNS of EAE mice. On the other hand, recombinant mouse p40(2) increased the infiltration of mononuclear cells into the CNS, enhanced the permeability through BBB and BSB, stimulated CNS expression of proinflammatory molecules, and aggravated the disease process of EAE. Taken together, our results suggest that p40(2) participates in the pathogenesis of EAE and that neutralization of p40(2) may be beneficial in multiple sclerosis patients.