title: Long-lasting immune responses 4 years after GAD-alum treatment in children with type 1 diabetes.
abstract: 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.
authors.affiliation: Division of Paediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. stina.axelsson@liu.se
authors.forename: Stina
authors.initials: S
authors.lastname: Axelsson
authors.forename: Mikael
authors.initials: M
authors.lastname: Chéramy
authors.forename: Maria
authors.initials: M
authors.lastname: Hjorth
authors.forename: Mikael
authors.initials: M
authors.lastname: Pihl
authors.forename: Linda
authors.initials: L
authors.lastname: Akerman
authors.forename: Emanuela
authors.initials: E
authors.lastname: Martinuzzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Mallone
authors.forename: Johnny
authors.initials: J
authors.lastname: Ludvigsson
authors.forename: Rosaura
authors.initials: R
authors.lastname: Casas
mesh_terms: D000293:Adolescent; D000536:Aluminum Hydroxide / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D000536:Aluminum Hydroxide; D005968:Glutamate Decarboxylase