Reversal of type 1 diabetes by a new MHC II-peptide chimera: "Single-epitope-mediated suppression" to stabilize a polyclonal autoimmune T-cell process.

Abstract

Polyclonality of self-reactive CD4(+) T cells is the hallmark of several autoimmune diseases like type 1 diabetes. We have previously reported that a soluble dimeric MHC II-peptide chimera prevents and reverses type 1 diabetes induced by a monoclonal diabetogenic T-cell population in double Tg mice [Casares, S. et al., Nat. Immunol. 2002. 3: 383-391]. Since most of the glutamic acid decarboxylase 65 (GAD65)-specific CD4(+) T cells in the NOD mouse are tolerogenic but unable to function in an autoimmune environment, we have activated a silent, monoclonal T-regulatory cell population (GAD65(217-230)-specific CD4(+) T cells) using a soluble I-A(αβ) (g7)/GAD65(217-230)/Fcγ2a dimer, and measured the effect on the ongoing polyclonal diabetogenic T-cell process. Activated GAD65(217-230)-specific T cells and a fraction of the diabetogenic (B(9-23)-specific) T cells were polarized toward the IL-10-secreting T-regulatory type 1-like function in the pancreas of diabetic NOD mice. More importantly, this led to the reversal of hyperglycemia for more than 2 months post-therapy in 80% of mice in the context of stabilization of pancreatic insulitis and improved insulin secretion by the β cells. These findings argue for the stabilization of a polyclonal self-reactive T-cell process by a single epitope-mediated bystander suppression. Dimeric MHC class II-peptide chimeras-like approach may provide rational grounds for the development of more efficient antigen-specific therapies in type 1 diabetes.

• Authors: Marvin Lin, Cristina Stoica-Nazarov, Jacqueline Surls, Margaret Kehl, Constantin Bona, Cara Olsen, Teodor D Brumeanu, Sofia Casares
• Journal: European journal of immunology (Eur J Immunol) Vol. 40 Issue 8 Pg. 2277-88 (Aug 2010) ISSN: 1521-4141 [Electronic] Germany
• PMID: 20540111 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes, T-Lymphocyte
• Fc gamma receptor IIA
• Histocompatibility Antigens Class II
• Insulin
• Peptide Fragments
• Receptors, IgG
• Recombinant Fusion Proteins
• insulin B (9-23)
• Interleukin-10
• GAD65 (217-236)
• Glutamate Decarboxylase

Topics

• Animals
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism, pathology)
• Clone Cells
• Diabetes Mellitus, Type 1 (immunology, pathology, physiopathology, therapy)
• Epitopes, T-Lymphocyte (genetics, metabolism)
• Glutamate Decarboxylase (genetics, metabolism)
• Histocompatibility Antigens Class II (metabolism)
• Hyperglycemia
• Immunosuppression Therapy
• Insulin (genetics, metabolism)
• Interleukin-10 (biosynthesis, genetics, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, Transgenic
• Pancreas (pathology)
• Peptide Fragments (genetics, metabolism)
• Receptors, IgG (genetics, metabolism)
• Recombinant Fusion Proteins (administration & dosage, genetics, metabolism)
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism, pathology)