Abstract
Tissue-specific autoimmune diseases such as type 1 diabetes (T1D) are characterized by T cell-driven pathology. Administration of autoantigenic peptides provides a strategy to selectively target the pathogenic T cell response. Indeed, treatment with beta cell peptides effectively prevents T1D in NOD mice. However, the efficacy of peptide immunotherapy generally wanes as beta cell autoimmunity progresses and islet inflammation increases. With the goal of enhancing the efficacy of peptide immunotherapy, soluble (s)IA(g7)-Ig dimers covalently linked to beta cell autoantigen-derived peptides were tested for the capacity to suppress late preclinical T1D. NOD female mice with established beta cell autoimmunity were vaccinated i.v. with a short course of sIA(g7)-Ig dimers tethered to peptides derived from glutamic acid decarboxylase (GAD)65 (sIA(g7)-pGAD65). Treatment with sIA(g7)-pGAD65 dimers and the equivalent of only approximately 7 microg of native peptide effectively blocked the progression of insulitis and the development of diabetes. Furthermore, suppression of T1D was dependent on beta cell-specific IL-10-secreting CD4+ T cells, although the frequency of GAD65-specific FoxP3-expressing CD4+ T cells was also increased in sIA(g7)-pGAD65 dimer vaccinated NOD mice. These results demonstrate that MHC class II-Ig dimer vaccination is a robust approach to suppress ongoing T cell-mediated autoimmunity, and may provide a superior strategy of adjuvant-free peptide-based immunotherapy to induce immunoregulatory T cells.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adoptive Transfer
-
Animals
-
Cell Differentiation / immunology
-
Diabetes Mellitus, Type 1 / immunology*
-
Diabetes Mellitus, Type 1 / pathology
-
Diabetes Mellitus, Type 1 / prevention & control*
-
Dimerization
-
Epitopes, T-Lymphocyte / administration & dosage*
-
Epitopes, T-Lymphocyte / genetics
-
Epitopes, T-Lymphocyte / immunology*
-
Female
-
Glutamate Decarboxylase / administration & dosage
-
Glutamate Decarboxylase / genetics
-
Glutamate Decarboxylase / immunology
-
Histocompatibility Antigens Class II / administration & dosage*
-
Histocompatibility Antigens Class II / genetics
-
Histocompatibility Antigens Class II / immunology*
-
Insulin-Secreting Cells / immunology
-
Insulin-Secreting Cells / pathology
-
Mice
-
Mice, Inbred NOD
-
Mice, SCID
-
Mice, Transgenic
-
Peptide Fragments / administration & dosage
-
Peptide Fragments / genetics
-
Peptide Fragments / immunology
-
Recombinant Fusion Proteins / administration & dosage
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / immunology
-
T-Lymphocytes, Regulatory / immunology*
-
T-Lymphocytes, Regulatory / pathology
-
T-Lymphocytes, Regulatory / transplantation
-
Vaccines, Subunit / administration & dosage
-
Vaccines, Subunit / genetics
-
Vaccines, Subunit / immunology
-
Vaccines, Synthetic / administration & dosage
-
Vaccines, Synthetic / genetics
-
Vaccines, Synthetic / immunology
Substances
-
Epitopes, T-Lymphocyte
-
Histocompatibility Antigens Class II
-
I-A g7 antigen
-
Peptide Fragments
-
Recombinant Fusion Proteins
-
Vaccines, Subunit
-
Vaccines, Synthetic
-
GAD65 (217-236)
-
Glutamate Decarboxylase