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IL-23 Is Critical in the Induction but Not in the Effector Phase of Experimental Autoimmune Encephalomyelitis

Paresh Thakker^1,*, Michael W. Leach^2,, Wen Kuang^2,, Stephen E. Benoit^*, John P. Leonard^3,4,* and Suzana Marusic^4,*

^* Department of Inflammation, Wyeth Research, Cambridge, MA 02140; Exploratory Drug Safety, Wyeth Research, Andover, MA 01810; and Department of Genetics, Wyeth Research, Andover, MA 01810

Experimental autoimmune encephalomyelitis (EAE), a T cell-mediated inflammatory disease of the CNS, is a rodent model of human multiple sclerosis. IL-23 is one of the critical cytokines in EAE development and is currently believed to be involved in the maintenance of encephalitogenic responses during the tissue damage effector phase of the disease. In this study, we show that encephalitogenic T cells from myelin oligodendrocyte glycopeptide (MOG)-immunized wild-type (WT) mice caused indistinguishable disease when adoptively transferred to WT or IL-23-deficient (p19 knockout (KO)) recipient mice, demonstrating that once encephalitogenic cells have been generated, EAE can develop in the complete absence of IL-23. Furthermore, IL-12/23 double-deficient (p35/p19 double KO) recipient mice developed EAE that was indistinguishable from WT recipients, indicating that IL-12 did not compensate for IL-23 deficiency during the effector phase of EAE. In contrast, MOG-specific T cells from p19KO mice induced EAE with delayed onset and much lower severity when transferred to WT recipient mice as compared with the EAE that was induced by cells from WT controls. MOG-specific T cells from p19KO mice were highly deficient in the production of IFN-, IL-17A, and TNF, indicating that IL-23 plays a critical role in development of encephalitogenic T cells and facilitates the development of T cells toward both Th1 and Th17 pathways.

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 Address correspondence and reprint requests to Dr. Paresh Thakker, Department of Inflammation, Wyeth Research, 200 Cambridgepark Drive, Cambridge, MA 02140. E-mail address: pthakker{at}wyeth.com

² M.W.L. and W.K. contributed equally to this research.

³ Current address: Genzyme Drug Discovery and Development, Waltham, MA 02451.

⁴ J.P.L. and S.M. contributed equally to this research.

⁵ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; MOG, myelin oligodendrocyte glycoprotein; CBA, cytometric bead assay; WT, wild type; KO, knockout mice; DKO, double KO; ES, embryonic stem; BAC, bacterial artificial chromosome.

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