title: High T cell responses to the glutamic acid decarboxylase (GAD) isoform 67 reflect a hyperimmune state that precedes the onset of insulin-dependent diabetes.
abstract: Pancreatic islet beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) is an autoimmune T cell-mediated process. Peripheral blood T cells, which proliferate to islet antigens such as glutamic acid decarboxylase (GAD), (pro)insulin or tyrosine phosphatase IA-2, can be detected in at-risk, first degree relatives of people with IDDM. However, cross-sectional studies cannot define the relationship between T cell responses and progression to IDDM. Longitudinal studies were therefore undertaken on 50 at-risk, first degree relatives tested at least yearly for up to 4 years, during which time five developed IDDM. Peripheral blood T cell responses to a GAD67(aa208-404)-glutathione-S-transferase (GST) fusion protein, GST, insulin and tetanus toxoid were measured, together with antibodies to islet cells, GAD, insulin and IA-2. High levels of antibodies to GAD or insulin were generally associated with low T cell responses to these antigens. Relatives who developed IDDM were characterized by high levels of antibodies to insulin and/or islet cells, and high T cell responses to GAD67-GST and tetanus, but not insulin, in the 24 months before clinical diagnosis. Cross-sectionally, T cell responses to GAD67(aa208-404)-GST and to full-length GAD65-GST were highly correlated (r=0.75, P<0.002). In conclusion, increased cellular immunity to the mid region of GAD67 was a marker of late pre-clinical IDDM, but appears to reflect a more general, transient state of cellular immune hyperresponsiveness.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital Post Office, Parkville, Victoria, Australia.
authors.forename: M C
authors.initials: MC
authors.lastname: Honeyman
authors.forename: N
authors.initials: N
authors.lastname: Stone
authors.forename: H
authors.initials: H
authors.lastname: de Aizpurua
authors.forename: M J
authors.initials: MJ
authors.lastname: Rowley
authors.forename: L C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001324:Autoantigens; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000209:etiology / Q000276:immunology*; D018450:Disease Progression; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology; D007527:Isoenzymes / Q000276:immunology*; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology; D008875:Middle Aged; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013601:T-Lymphocytes / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D006680:HLA Antigens; D007328:Insulin; D007527:Isoenzymes; D008565:Membrane Proteins; D013745:Tetanus Toxoid; C024211:islet cell antibody; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase