Role of the IL-12/IL-23 system in the regulation of T-cell responses in central nervous system inflammatory demyelination.

Interleukin-12 (IL-12) has long been considered essential in T-cell-mediated autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). This is based on the strong capacity of IL-12 to induce T-cell activation and Th1 differentiation. However, recent data have shown that the perceived central role of IL-12 in CNS inflammatory demyelination is actually due to IL-23, a closely related cytokine sharing the p40 subunit and the beta1 receptor chain with IL-12. There appear to be three different aspects of IL-12 involvement in EAE: (1) disease-promoting effects of exogenous IL-12, particularly in relapsing-remitting EAE and adoptive transfer EAE; (2) lack of IL-12 requirement in EAE pathogenesis, as indicated by studies in knockout mice; and (3) immunoregulatory effects of IL-12. Together, these observations make IL-12 a less attractive target for therapeutic intervention in MS. IL-23 neutralization may be a better candidate for therapeutic intervention, and it remains to be established whether blocking IL-23 with antibodies in adult mice will have the same effects as knocking out the IL-23p19 gene. Current clinical trials of neutralizing anti-IL-12 antibodies in other immune-mediated diseases target the p40 subunit, thereby neutralizing both IL-12 and IL-23. Thus, new experimental data are expected to have important implications for therapy of human diseases.