Insulin-dependent diabetes mellitus
Harrison LC, Colman PG
Current Therapeutics 38:13-23
IDDM is one of the most common chronic diseases that begin in childhood, being more frequent than cancer in this age group. Recent studies indicate, however, that up to 1/3 of cases present after adolescence.
Strategies for identifying and predicting islet autoantigen T-cell epitopes in insulin-dependent diabetes
Honeyman MC, Brusic V, Harrison LC
Ann Med 29:402-404 (1997)
T cells recognize peptide epitopes bound to major histocompatibility complex molecules. Human T-cell epitopes have diagnostic and therapeutic applications in autoimmune diseases. However, their accurate definition within an autoantigen by T-cell bioassay, usually proliferation, involves many costly peptides and a large amount of blood. We have therefore developed a strategy to predict T-cell epitopes and applied it to tyrosine phosphatase IA-2, an autoantigen in IDDM, and HLA-DR4(*0401). First, the binding of synthetic overlapping peptides encompassing IA-2 was measured directly to purified DR4. Secondly, a large amount of HLA-DR4 binding data were analysed by alignment using a genetic algorithm and were used to train an artificial neural network to predict the affinity of binding. This bioinformatic prediction method was then validated experimentally and used to predict DR4 binding peptides in IA-2. The binding set encompassed 85% of experimentally determined T-cell epitopes. Both the experimental and bioinformatic methods had high negative predictive values, 92% and 95%, indicating that this strategy of combining experimental results with computer modelling should lead to a significant reduction in the amount of blood and the number of peptides required to define T-cell epitopes in humans.
High T-cell responses to the glutamic acid decarboxylase (GAD) isoform 67 reflect a hyperimmune state that precedes the onset of insulin-dependent diabetes
Honeyman MC, Stone N, DeAizpurua HJ, Rowley MJ, Harrison LC
J Autoimmun 10:165-173 (1997)
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.
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Immunology of type 1 diabetes
Noorchashm H, Kwok W, Rabinovitch A, Harrison LC
Diabetologia 40:B50-B57 (1997)
Insulin-dependent diabetes mellitus (IDDM) is at the
forefront as a paradigm for research on polygenic disorders
and on the early diagnosis, prediction and prevention
of autoimmune disease. There is growing anticipation
that knowledge of the genetic susceptibility
and processes of beta-cell destruction, gained over
the past two decades, herald an era of targeted therapy
for the prevention of IDDM; and without prevention
there can be no cure. The genetic dissection of
IDDM and the molecular immunology of IDDM are
converging on the functional mechanisms by which
IDDM susceptibility gene products contribute to disease
pathogenesis. This is illustrated by the role of the
HLA-DQ8 (3.2) antigen-presenting molecule and its
counterpart, I-Ag7, in the NOD mouse model of
IDDM. Increasing evidence supports the determinant
selection model for MHC susceptibility molecules
such as HLA-DQ8 (or protective molecules
such as DQ6) in which these molecules bind specific
peptides that regulate T-cell immunity against pancreatic
beta-cells. The appeal of this model is that it
identifies not only pathogenic T-cell epitopes but
peptides that have potential as immunotherapeutic
agents. Already, peptides restricted by I-Ag7 have
been shown to be immunoregulatory when administered,
e. g. transmucosally, in the NOD mouse. The functional consequence of T-cell receptor recognition
of peptide-MHC complexes, i. e. the nature of the Tcell
response, is determined in the first instance by
the peptide antigen itself and the avidity of its interaction.
Given the tremendous advances in the immunology
and genetics of IDDM, and the techniques now at
our disposal, it is appropriate to further strengthen
the marriage between basic research and clinical application.
