Altered B:9-23 insulin, when administered intranasally with cholera toxin adjuvant, suppresses the expression of insulin autoantibodies and prevents diabetes.
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.
First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Masakazu
M
Kobayashi
Norio
N
Abiru
Takeshi
T
Arakawa
Keiko
K
Fukushima
Hongbo
H
Zhou
Eiji
E
Kawasaki
Hironori
H
Yamasaki
Edwin
E
Liu
Dongmei
D
Miao
F Susan
FS
Wong
George S
GS
Eisenbarth
Katsumi
K
Eguchi
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects* / Q000276:immunology; D001324:Autoantigens / Q000008:administration & dosage* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002772:Cholera Toxin / Q000008:administration & dosage* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006943:Hyperglycemia / Q000276:immunology / Q000517:prevention & control; D007108:Immune Tolerance / Q000187:drug effects*; D007328:Insulin / Q000008:administration & dosage* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD
D000276:Adjuvants, Immunologic; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D007328:Insulin; D002772:Cholera Toxin