International Immunology, Vol 10, 1765-1776, Copyright © 1998 by Oxford University Press
RJ Boyton, T Lohmann, M Londei, H Kalbacher, T Halder, AJ Frater, DC Douek, DG Leslie, RA Flavell and DM Altmann
Glutamic acid decarboxylase (GAD65) has been implicated as a targeted self
antigen in the immune destruction of pancreatic beta cells. T cell
responses to GAD65 peptides have been detected in both patients with type I
diabetes and in the non-obese diabetic (NOD) mouse. To establish which
GAD65 epitopes are important in the immunopathogenesis of disease we
initially compared T cell responses to GAD65 epitopes in conditions of
disease susceptibility and protection. T cell responses to GAD65 peptides
were measured in monozygotic twin pairs selected on the basis of disease
discordance and T cell recognition of immunogenic regions of GAD65.
Peptides of interest were then used to immunize susceptible NOD mice and
H2-E transgenic NOD mice which are protected from diabetes. A differential
response to the epitope GAD65 521-535 discriminated diabetic from
non-diabetic human twins as well as susceptible from protected mice. This
epitope as well as GAD 505-519 induces T cell responses despite binding the
type I diabetes associated HLA- DQA1*0301/DQB1*0302 product with low
affinity. Since DQ-restricted T cell responses are difficult to study in
humans, HLA-DQ8 transgenic mice were then used: GAD epitopes 521-535 and
505-519 induced responses in DQ8 transgenic mice and T cell lines were
established. Long-term T cell lines against GAD 505-519 were HLA-DQ
restricted, and responded to peptide with a strong IFN-gamma and IL-10
response. The findings implicate GAD 521-535 as a possible target peptide
in pathogenesis and are compatible with a model whereby self-reactive T
cells specific for low-affinity peptide-MHC complexes may escape thymic
negative selection.
ARTICLES
Glutamic acid decarboxylase T lymphocyte responses associated with susceptibility or resistance to type I diabetes: analysis in disease discordant human twins, non-obese diabetic mice and HLA-DQ transgenic mice
Transplantation Biology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
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