Reversal of type 1 diabetes by a new MHC II-peptide chimera: "Single-epitope-mediated suppression" to stabilize a polyclonal autoimmune T-cell process.
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.
Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA.
Marvin
M
Lin
Cristina
C
Stoica-Nazarov
Jacqueline
J
Surls
Margaret
M
Kehl
Constantin
C
Bona
Cara
C
Olsen
Teodor D
TD
Brumeanu
Sofia
S
Casares
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006943:Hyperglycemia; D007165:Immunosuppression Therapy; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D018984:Epitopes, T-Lymphocyte; C080568:Fc gamma receptor IIA; D000949:Histocompatibility Antigens Class II; D007328:Insulin; D010446:Peptide Fragments; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C097877:insulin B (9-23); D016753:Interleukin-10; C439756:GAD65 (217-236); D005968:Glutamate Decarboxylase