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Functional Blocking Monoclonal Antibodies against IL-12p40 Homodimer Inhibit Adoptive Transfer of Experimental Allergic Encephalomyelitis ¹

Department of Neurological Sciences, Division of Neuroscience, Rush University Medical Center, Chicago, IL 60612

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 (p40₂) was considered as an inactive or inhibitory molecule and its functions are poorly understood. To facilitate the studies on p40₂, we have recently generated neutralizing mAb against mouse p40₂. The present study demonstrates the effectiveness of p40₂ mAb in treating the disease process of relapsing-remitting EAE in female SJL/J mice. The p40₂ 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 p40₂ 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, p40₂ 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 p40₂ 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 p40₂ participates in the pathogenesis of EAE and that neutralization of p40₂ may be beneficial in multiple sclerosis patients.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grants (NS39940 and NS48923).

² Address correspondence and reprint requests to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 320, Chicago, IL 60612. E-mail address: kpahan{at}rush.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; EAE. experimental allergic encephalomyelitis; BBB, blood-brain barrier; PLP, proteolipid protein; iNOS, inducible NO synthase; MBP, myelin basic protein; dpt, day posttransfer; BSB, blood-spinal cord barrier; MOG, myelin oligodendrocyte glycoprotein; RR, relapsing-remitting.