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A Fusion Protein Consisting of IL-16 and the Encephalitogenic Peptide of Myelin Basic Protein Constitutes an Antigen-Specific Tolerogenic Vaccine That Inhibits Experimental Autoimmune Encephalomyelitis¹

Department of Microbiology and Immunology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834

To test a novel concept for the generation of tolerogenic vaccines, fusion proteins were constructed encompassing a tolerogenic or biasing cytokine and the major encephalitogenic peptide of guinea pig myelin basic protein (GPMBP; i.e., neuroantigen or NAg). The cytokine domain was predicted to condition APC while simultaneously targeting the covalently linked encephalitogenic peptide to the MHC class II Ag processing pathway of those conditioned APC. Rats were given three s.c. injections of cytokine-NAg in saline 1–2 wk apart and then at least 1 wk later were challenged with NAg in CFA. The rank order of tolerogenic activity in the Lewis rat model of EAE was NAgIL16 > IL2NAg > IL1RA-NAg, IL13NAg IL10NAg, GPMBP, GP69–88, and saline. NAgIL16 was also an effective inhibitor of experimental autoimmune encephalomyelitis when administered after an encephalitogenic challenge during the onset of clinical signs. Covalent linkage of the NAg and IL-16 was required for inhibition of experimental autoimmune encephalomyelitis. These data identify IL-16 as an optimal cytokine partner for the generation of tolerogenic vaccines and indicate that such vaccines may serve as Ag-specific tolerogens for the treatment of autoimmune disease.

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 study was supported by a research grant from the National Multiple Sclerosis Society.

² Address correspondence and reprint requests to Dr. Mark D. Mannie, Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834. E-mail address: manniem{at}ecu.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; DHFR, dihydrofolate reductase; Ekdel, deletion of the enterokinase cleavage site; GPMBP, guinea pig myelin basic protein; MBP, myelin basic protein; MHCII, MHC class II glycoprotein; NAg, neuroantigen.

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				M. D. Mannie, D. J. Abbott, and J. L. Blanchfield Experimental Autoimmune Encephalomyelitis in Lewis rats: IFN-{beta} Acts As a Tolerogenic Adjuvant for Induction of Neuroantigen-Dependent Tolerance J. Immunol., May 1, 2009; 182(9): 5331 - 5341. [Abstract] [Full Text] [PDF]