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Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, NC 27834
The purpose of this study was to assess whether the Ag-targeting activity of cytokine/neuroantigen (NAg) fusion proteins may be associated with mechanisms of tolerance induction. To assess this question, we expressed fusion proteins comprised of a N-terminal cytokine domain and a C-terminal NAg domain. The cytokine domain comprised either rat IL-2 or IL-4, and the NAg domain comprised the dominant encephalitogenic determinant of the guinea pig myelin basic protein. Subcutaneous administration of IL2NAg (IL-2/NAg fusion protein) into Lewis rats either before or after an encephalitogenic challenge resulted in an attenuated course of experimental autoimmune encephalomyelitis. In contrast, parallel treatment of rats with IL4NAg (IL-4/NAg fusion protein) or NAg lacked tolerogenic activity. In the presence of IL-2R+ MHC class II+ T cells, IL2NAg fusion proteins were at least 1,000 times more potent as an Ag than NAg alone. The tolerogenic activity of IL2NAg in vivo and the enhanced potency in vitro were both dependent upon covalent linkage of IL-2 and NAg. IL4NAg also exhibited enhanced antigenic potency. IL4NAg was 
100-fold more active than NAg alone in the presence of splenic APC. The enhanced potency of IL4NAg also required covalent linkage of cytokine and NAg and was blocked by soluble IL-4 or by a mAb specific for IL-4. Other control cytokine/NAg fusion proteins did not exhibit a similar enhancement of Ag potency compared with NAg alone. Thus, the IL2NAg and IL4NAg fusion proteins targeted NAg for enhanced presentation by particular subsets of APC. The activities of IL2NAg revealed a potential relationship between NAg targeting to activated T cells, T cell-mediated Ag presentation, and tolerance induction.
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, East Carolina University School of Medicine, Greenville, NC 27834. E-mail address: manniem{at}ecu.edu
3 Abbreviations used in this paper: T-APC, T cell APC; DHFR, dihydrofolate reductase; EAE, experimental autoimmune encephalomyelitis; GPMBP, guinea pig myelin basic protein; IL2EKdel, IL2NAg fusion protein with deletion of the enterokinase cleavage site; IL2NAg, IL-2/neuroantigen fusion protein; IL4NAg, IL-4/neuroantigen fusion protein; MHCII, MHC class II glycoprotein; MBP, myelin basic protein; NAg, neuroantigen; EK, enterokinase cleavage site.
This article has been cited by other articles:
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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]
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M. D. Mannie and D. J. Abbott 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 Encephalomyelitis J. Immunol., August 1, 2007; 179(3): 1458 - 1465. [Abstract] [Full Text] [PDF]
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