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Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107
IL-27 has been shown to play a suppressive role in experimental autoimmune encephalomyelitis (EAE) as demonstrated by more severe disease in IL-27R-deficient (WSX-1–/–) mice. However, whether IL-27 influences the induction or effector phase of EAE is unknown. This is an important question as therapies for autoimmune diseases are generally started after autoreactive T cells have been primed. In this study, we demonstrate maximal gene expression of IL-27 subunits and its receptor in the CNS at the effector phases of relapsing-remitting EAE including disease peak and onset of relapse. We also show that activated astrocyte cultures secrete IL-27p28 protein which is augmented by the endogenous factor, IFN-
. To investigate functional significance of a correlation between gene expression and disease activity, we examined the effect of IL-27 at the effector phase of disease using adoptive transfer EAE. Exogenous IL-27 potently suppressed the ability of encephalitogenic lymph node and spleen cells to transfer EAE. IL-27 significantly inhibited both nonpolarized and IL-23-driven IL-17 production by myelin-reactive T cells thereby suppressing their encephalitogenicity in adoptive transfer EAE. Furthermore, we demonstrate a strong suppressive effect of IL-27 on active EAE in vivo when delivered by s.c. osmotic pump. IL-27-treated mice had reduced CNS inflammatory infiltration and, notably, a lower proportion of Th17 cells. Together, these data demonstrate the suppressive effect of IL-27 on primed, autoreactive T cells, particularly, cells of the Th17 lineage. IL-27 can potently suppress the effector phase of EAE in vivo and, thus, may have therapeutic potential in autoimmune diseases such as multiple sclerosis.
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 work was supported by grants from the National Institutes of Health, the National Multiple Sclerosis Society (NMSS), and Commonwealth of Pennsylvania Department of Health (to A.R.) and by a postdoctoral fellowship (to D.C.F.) from the National Multiple Sclerosis Society.
2 Current address: Division of Clinical Neurology, Nottingham University Hospitals, Queen’s Medical Centre Campus, Nottingham NG7 2UH, U.K.
3 Address correspondence and reprint requests to Dr. Abdolmohamad Rostami, Department of Neurology, Thomas Jefferson University, Suite 300 JHN, 900 Walnut Street, Philadelphia, PA 19107. E-mail address: a.m.rostami{at}jefferson.edu
4 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; RR, relapsing-remitting; MOG, myelin oligodendrocyte glycoprotein; DLN, draining lymph node; rm, recombinant murine; CBA, cytometric bead array; LFB, Luxol Fast Blue; SOCS, suppressor of cytokine signaling.
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