title: Anti-idiotypic antibody specific to GAD65 autoantibody prevents type 1 diabetes in the NOD mouse.
abstract: Overt autoantibodies to the smaller isoform of glutamate decarboxylase (GAD65Ab) are a characteristic in patients with Type 1 diabetes (T1D). Anti-idiotypic antibodies (anti-Id) directed to GAD65Ab effectively prevent the binding of GAD65 to GAD65Ab in healthy individuals. Levels of GAD65Ab-specific anti-Id are significantly lower in patients with T1D, leading to overt GAD65Ab in these patients. To determine the possible protective role of GAD65Ab-specific anti-Id in T1D pathogenesis, we developed the monoclonal anti-Id MAb 8E6G4 specifically targeting human monoclonal GAD65Ab b96.11. MAb 8E6G4 was demonstrated as a specific anti-Id directed to the antigen binding site of b96.11. MAb 8E6G4 recognized human antibodies in sera from healthy individuals, T2D patients, and T1D patients as established by ELISA. We confirmed these MAb 8E6G4-bound human antibodies to contain GAD65Ab by testing the eluted antibodies for binding to GAD65 in radioligand binding assays. These findings confirm that GAD65Ab are present in sera of individuals, who test GAD65Ab-negative in conventional detection assays. To test our hypothesis that GAD65Ab-specific anti-Id have an immune modulatory role in T1D, we injected young Non Obese Diabetic (NOD) mice with MAb 8E6G4. The animals were carefully monitored for development of T1D for 40 weeks. Infiltration of pancreatic islets by mononuclear cells (insulitis) was determined to establish the extent of an autoimmune attack on the pancreatic islets. Administration of MAb 8E6G4 significantly reduced the cumulative incidence rate of T1D and delayed the time of onset. Insulitis was significantly less severe in animals that received MAb 8E6G4 as compared to control animals. These results support our hypothesis that anti-Id specific to GAD65Ab have a protective role in T1D.
authors.affiliation: Department of Endocrinology, Jiangsu Province Hospital of TCM, Nanjing, Jiangsu, China. drwangxin@gmail.com
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Aixia
authors.initials: A
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Feng
authors.forename: Wenbin
authors.initials: W
authors.lastname: Shang
authors.forename: Marlena
authors.initials: M
authors.lastname: Maziarz
authors.forename: Jared
authors.initials: J
authors.lastname: Radtke
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001665:Binding Sites; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008875:Middle Aged; D020033:Protein Isoforms; D017422:Sequence Analysis, DNA
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D020033:Protein Isoforms; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2