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Altered B:9–23 Insulin, When Administered Intranasally with Cholera Toxin Adjuvant, Suppresses the Expression of Insulin Autoantibodies and Prevents Diabetes¹

Masakazu Kobayashi^2,*,, Norio Abiru^3,*, Takeshi Arakawa, Keiko Fukushima^*, Hongbo Zhou^*, Eiji Kawasaki, Hironori Yamasaki^*, Edwin Liu, Dongmei Miao, F. Susan Wong^¶, George S. Eisenbarth and Katsumi Eguchi^*

^* First Department of Internal Medicine and Department of Metabolism/Diabetes and Clinical Nutrition, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; Division of Molecular Microbiology, Center of Molecular Biosciences, University of the Ryukyus, Okinawa, Japan; Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, CO 80262; and ^¶ Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol, United Kingdom

Insulin peptide B:9–23 is a major autoantigen in type 1 diabetes that contains two distinct CD4 epitopes (B:9–16 and B:13–23). One of the two epitopes, B:13–23, overlaps with a CTL epitope (B:15–23). In this study, we report that the elimination of the CTL epitope from the B:9–23 peptide by amino acid substitution (with alanine) at positions B:16 and 19 (A16,19 altered peptide ligand) or truncation of the C-terminal amino acids from the peptide (B:9–21), neither of which stimulated the proliferation of insulin B:15–23 reactive CD8 T cells, provided significant intranasally induced suppression of diabetes when coadministered with a potent mucosal adjuvant cholera toxin (CT). Intranasal treatment with A16,19 resulted in the elimination of spontaneous insulin autoantibodies, significant inhibition of insulitis and remission from hyperglycemia, and prevented the progression to diabetes. Intranasal administration of native B:9–23/CT or B:11–23/CT resulted in a significant enhancement of insulin autoantibody expression and severity of insulitis and failed to prevent diabetes. Our present study indicates that elimination of the CTL epitope from the B:9–23 peptide was critically important for mucosally induced diabetes prevention. The A16,19 altered peptide ligand, but not other native insulin peptides, suppresses insulin autoantibodies associated with protection from and remission of diabetes.

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 research grants from Japan Society for the Promotion of Science (17590940), the Japan Diabetes Foundation (No. 14–55), and in part by a Grant-in-Aid for Scientific Research from Nagasaki University, Nagasaki, Japan.

² Current address: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, CO 80262.

³ Address correspondence and reprint requests to Dr. Norio Abiru, First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto, Nagasaki, Japan. E-mail address: f1931{at}cc.nagasaki-u.ac.jp

⁴ Abbreviations used in this paper: B:9–23, insulin B chain peptide with aa 9–23; APL, altered peptide ligand; A16,19 APL, APL with alanine substitutions at positions 16 and 19; CT, cholera toxin; IAA, insulin autoantibody; TT, tetanus toxin.