Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodies.
Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b96.11) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b96.11 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b96.11 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b96.11 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne.
Hall
Tyler R
TR
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Bogdani
Marika
M
Leboeuf
Renee C
RC
Kirk
Elizabeth A
EA
Maziarz
Marlena
M
Banga
J Paul
JP
Oak
Shilpa
S
Pennington
Christina A
CA
Hampe
Christiane S
CS
D000595:Amino Acid Sequence; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D001667:Binding, Competitive; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000939:Epitopes / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D012720:Severity of Illness Index; D015431:Weight Loss
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000939:Epitopes; D007074:Immunoglobulin G; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2