Establishing a role for IL-27 in the amelioration of MS and EAE.

摘要

IL-27 is an immunomodulatory cytokine with both pro- and anti- inflammtory effects under different conditions. Exogenous IL-27 suppresses EAE; thus the goal of this project is to determine the role of IL-27 in two different models of ameliorated EAE and the treatment of MS by IFN-β. The first model of ameliorated EAE involves immature mice. MS is rare in young people and EAE has reduced susceptibility among young mice. We characterized this phenomenon in four week old C57BL/6 mice and transferred encephalitogenic immune cells from mice immunized for EAE into recipient mice of different ages and found that the age of the immune system determines susceptibility to EAE, not the age of the target organ. IL-27R&agr;-/- mice do not demonstrate reduced susceptibility to EAE in young mice. Building on this foundation, the investigation moved to the role of IL-27 in i.v. induction of tolerance. Administration of myelin antigen i.v. leads to antigen specific tolerance and amelioration of clinical EAE. IL-27 is upregulated after i.v. induction of tolerance suggesting a role in this process. While wildtype mice experience significant amelioration of EAE following induction of i.v. toleralance, IL-27R&agr;-/- mice experience no alteration in disease severity. Upregulation of the anti-inflammatory cytokine IL-10 was the only marker of tolerance observed in wildtype mice at all three time points and never observed in the IL-27R&agr;-/- mice suggesting a role for IL-27 driven IL-10 production in i.v. induction of tolerance. Building on these results, we next examined the role of IL-27 in the treatment of EAE by IFN-β. Previous studies demonstrated that IL-27 and IFN-β have similar effects on murine T cells which is here confirmed in human T cells. After demonstrating that IFN-β drives IL-17 production from human immune cells; we demonstrated that IFN-β driven IL-27 production is required for IFN-β mediated upregulation of IL-10. Despite these findings, IFN-β is an effective treatment for EAE in IL-27R&agr;-/- mice and suppresses IL-17 in humans independently of IL-27. In conclusion, IL-27 is a potent anti-inflammatory cytokine involved in several models of ameliorated EAE; however, it is unlikely to be involved in the treatment of MS by IFN-β.