Administration of a determinant of preproinsulin can induce regulatory T cells and suppress anti-islet autoimmunity in NOD mice

Takashi Arai; Hiroaki Moriyama; Mami Shimizu; Hirotomo Sasaki; Minoru Kishi; Yasuyo Okumachi; Hisafumi Yasuda; Kenta Hara; Koichi Yokono; Masao Nagata

doi:10.1016/j.clim.2010.02.016

Administration of a determinant of preproinsulin can induce regulatory T cells and suppress anti-islet autoimmunity in NOD mice

Clin Immunol. 2010 Jul;136(1):74-82. doi: 10.1016/j.clim.2010.02.016. Epub 2010 Apr 1.

Authors

Takashi Arai¹, Hiroaki Moriyama, Mami Shimizu, Hirotomo Sasaki, Minoru Kishi, Yasuyo Okumachi, Hisafumi Yasuda, Kenta Hara, Koichi Yokono, Masao Nagata

Affiliation

¹ Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

PMID: 20359955
DOI: 10.1016/j.clim.2010.02.016

Abstract

Antigen-specific immunotherapy is expected to be an ideal strategy for treating type 1 diabetes (T1D). We investigated the therapeutic efficacy of a peptide in the leader sequence of preproinsulin, which was selected because of its binding affinity to the MHC I-A(g7) molecule. Preproinsulin-1 L7-24 peptide (L7-24) emulsified in Freund's incomplete adjuvant was administered subcutaneously to NOD mice. Administration of L7-24 increased the proportion of regulatory T cells in the spleen. Splenocytes of NOD mice immunized with this peptide secreted IL-4 and IL-10 in response to L7-24. This peptide also significantly prevented the development of diabetes and cured some newly diabetic NOD mice without recurrence. L7-24 peptide, which has a high affinity for pockets of I-A(g7), induced regulatory T cells and showed therapeutic effects. This peptide may provide a new approach for developing antigen-specific immunotherapy for autoimmune diabetes.

MeSH terms

Amino Acid Sequence
Animals
Autoimmunity / immunology*
Blood Glucose / immunology
Blood Glucose / metabolism
Cell Count
Concanavalin A / pharmacology
Diabetes Mellitus, Type 1 / immunology
Diabetes Mellitus, Type 1 / pathology
Diabetes Mellitus, Type 1 / prevention & control
Diabetes Mellitus, Type 1 / therapy*
Female
Forkhead Transcription Factors / metabolism
Histocompatibility Antigens Class II / immunology
Histocompatibility Antigens Class II / metabolism
Immunotherapy, Active / methods*
Insulin / genetics
Insulin / immunology*
Interferon-gamma / metabolism
Interleukin-10 / metabolism
Interleukin-4 / metabolism
Islets of Langerhans / cytology
Islets of Langerhans / immunology*
Islets of Langerhans / pathology
Lymphocyte Activation / drug effects
Lymphocyte Activation / immunology
Mice
Mice, Inbred NOD
Mice, Knockout
Peptide Fragments / immunology*
Peptide Fragments / metabolism
Peptide Fragments / therapeutic use
Protein Binding / immunology
Protein Precursors / immunology*
Spleen / cytology
Spleen / immunology
T-Lymphocytes / drug effects
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Th2 Cells / immunology
Th2 Cells / metabolism
Transforming Growth Factor beta / metabolism
Vaccination

Substances

Blood Glucose
Forkhead Transcription Factors
Foxp3 protein, mouse
Histocompatibility Antigens Class II
Insulin
Peptide Fragments
Protein Precursors
Transforming Growth Factor beta
Concanavalin A
Interleukin-10
Interleukin-4
preproinsulin
Interferon-gamma