Long-lasting immune responses 4 years after GAD-alum treatment in children with type 1 diabetes.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Aluminum Hydroxide/*therapeutic use ; Diabetes Mellitus, Type 1/*drug therapy ; Diabetes Mellitus, Type 1/*immunology ; Glutamate Decarboxylase/*therapeutic use ; Immunity/*immunology; Adolescent ; Aluminum Hydroxide/blood ; Aluminum Hydroxide/pharmacology ; CD4-Positive T-Lymphocytes/cytology ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Proliferation/drug effects ; Child ; Cytokines/metabolism ; Diabetes Mellitus, Type 1/blood ; Gene Expression Regulation/drug effects ; Glutamate Decarboxylase/blood ; Glutamate Decarboxylase/pharmacology ; Humans ; Immunity/drug effects ; Immunologic Memory/drug effects ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Lymphocyte Count ; Real-Time Polymerase Chain Reaction

A phase II clinical trial with glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) has shown efficacy in preserving residual insulin secretion in children and adolescents with recent-onset type 1 diabetes (T1D). We have performed a 4-year follow-up study of 59 of the original 70 patients to investigate long-term cellular and humoral immune responses after GAD-alum-treatment. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with GAD(65). Frequencies of naïve, central and effector memory CD4+ and CD8+ T cells were measured, together with cytokine secretion, proliferation, gene expression and serum GAD(65) autoantibody (GADA) levels. We here show that GAD-alum-treated patients display increased memory T-cell frequencies and prompt T-cell activation upon in vitro stimulation with GAD(65), but not with control antigens, compared with placebo subjects. GAD(65)-induced T-cell activation was accompanied by secretion of T helper (Th) 1, Th2 and T regulatory cytokines and by induction of T-cell inhibitory pathways. Moreover, post-treatment serum GADA titres remained persistently increased in the GAD-alum arm, but did not inhibit GAD(65) enzymatic activity. In conclusion, memory T- and B-cell responses persist 4 years after GAD-alum-treatment. In parallel to a GAD(65)-induced T-cell activation, our results show induction of T-cell inhibitory pathways important for regulating the GAD(65) immunity.

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0 (Cytokines)
5QB0T2IUN0 (Aluminum Hydroxide)
EC 4.1.1.15 (Glutamate Decarboxylase)

Date Created: 20111217 Date Completed: 20120423 Latest Revision: 20211021

20221213

PMC3236224

10.1371/journal.pone.0029008

22174945