High T cell responses to the glutamic acid decarboxylase (GAD) isoform 67 reflect a hyperimmune state that precedes the onset of insulin-dependent diabetes

J Autoimmun. 1997 Apr;10(2):165-73. doi: 10.1006/jaut.1996.0124.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantibodies / biosynthesis
  • Autoantibodies / immunology
  • Autoantigens
  • Child
  • Diabetes Mellitus, Type 1 / enzymology*
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / immunology*
  • Disease Progression
  • Glutamate Decarboxylase / immunology*
  • HLA Antigens / genetics
  • Humans
  • Insulin / immunology
  • Islets of Langerhans / immunology
  • Isoenzymes / immunology*
  • Longitudinal Studies
  • Lymphocyte Activation*
  • Membrane Proteins / immunology
  • Middle Aged
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / immunology
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • T-Lymphocytes / immunology*
  • Tetanus Toxoid / immunology


  • Autoantibodies
  • Autoantigens
  • HLA Antigens
  • Insulin
  • Isoenzymes
  • Membrane Proteins
  • Tetanus Toxoid
  • islet cell antibody
  • PTPRN protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • Glutamate Decarboxylase