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.
Gran
Bruno
B
Department of Neurology, Thomas Jefferson University, 300 Jefferson Hospital for Neuroscience, 900 Walnut Street, Philadelphia, PA 19107, USA.
Zhang
Guang-Xian
GX
Rostami
Abdolmohamad
A
D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D018664:Interleukin-12 / Q000502:physiology*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000209:etiology / Q000276:immunology; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
C508438:IL12RB1 protein, human; C508840:IL23A protein, human; C508440:Il12rb1 protein, mouse; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12