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Experimental Autoimmune Encephalomyelitis in Lewis rats: IFN-β Acts As a Tolerogenic Adjuvant for Induction of Neuroantigen-Dependent Tolerance¹

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

Cytokine-Ag fusion proteins represent a novel approach for induction of Ag-specific tolerance and may constitute an efficient therapy for autoimmune disease. This study addressed whether a fusion protein containing rat IFN-β and the encephalitogenic 73–87 determinant of myelin basic protein (i.e., the neuroantigen, or NAg) could prevent or treat experimental autoimmune encephalomyelitis (EAE) in Lewis rats. The optimal structure of the fusion protein was comprised of the rat IFN-β cytokine as the N-terminal domain with an enterokinase (EK) linker to the NAg domain. Both cytokine and NAg domains had full biological activity. Subcutaneous administration of 1 nmol of IFNβ-NAg fusion protein in saline on days –21, –14, and –7 before encephalitogenic challenge on day 0 resulted in a substantial attenuation of EAE. In contrast, administration of IFN-β or NAg alone did not affect susceptibility to EAE. The covalent attachment of IFN-β and NAg was not necessary, because separate injections of IFN-β and NAg at adjacent sites were as effective as injection of IFNβ-NAg for prevention of disease. When treatment was initiated after disease onset, the rank order of inhibitory activity was as follows: the IFNβ-NAg fusion protein a mixture of IFN-β plus NAg > IFN-β > NAg. The novel finding that IFN-β acts as a tolerogenic adjuvant as well as a tolerogenic fusion partner may have significance for development of tolerogenic vaccines.

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 research grants from the National Multiple Sclerosis Society and the Brody Brothers Endowment Fund.

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

³ Abbreviations used in this paper: MS, multiple sclerosis; DHFR, dihydrofolate reductase; EAE, experimental autoimmune encephalomyelitis; EK, enterokinase; GPMBP, guinea pig myelin basic protein; MBP, myelin basic protein; MHC-I, MHC class I glycoprotein; MHC-II, MHC class II glycoprotein; NAg, neuroantigen (the encephalitogenic sequence of GPMBP; refers to the 73–87 peptide that was included in the IFNβ-NAg fusion protein; also refers to the gp69–88 synthetic peptide); 6his, 6-histidine.