Diminished IFN-gamma response to diabetes-associated autoantigens in children at diagnosis and during follow up of type 1 diabetes.
BACKGROUND
Imbalance of T-helper (Th)1- and Th2-like cytokines has been associated with type 1 diabetes. We therefore studied the immune deviation in antigen-specific T cells from diagnosis onwards in type 1 diabetic children.


METHODS
Peripheral blood mononuclear cells (PBMC) were collected from 15 children after 4 days, 3 months and 18 months of being diagnosed with type 1 diabetes, from 15 healthy children matched by age and gender to the type 1 diabetic children and from 14 children with and 35 children without HLA-risk genes. Secretion of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) was detected by ELISPOT after stimulation with glutamic acid decarboxylase (GAD(65), protein and aa 247-279), recombinant tyrosinphosphatase (IA-2), insulin, ovalbumin and phytohaemagglutinin (PHA).


RESULTS
Secretion of IFN-gamma in PBMC stimulated with GAD(65) (p < 0.05), the GAD(65)-peptide (p < 0.01), IA-2 (p < 0.01), and insulin (p < 0.01) was lower in diabetic children at diagnosis than in healthy children. Stimulation of PBMC with GAD(65) and IA-2 decreased the secretion of IFN-gamma in children with HLA-risk genotype. Spontaneous and antigen-induced IFN-gamma secretion increased significantly after diagnosis of the disease, but did not exceed the levels observed in healthy children. Fasting C-peptide levels at diagnosis correlated with insulin-induced IFN-gamma (R = 0.52; p = 0.05) and negatively with spontaneous IL-4 secretion (R = -0.62; p < 0.05).


CONCLUSIONS
A diminished IFN-gamma secretion and the association of fasting C-peptide levels with cytokine response in children with type 1 diabetes suggest that factors related to beta-cell function in type 1 diabetes may modify T-cell function. Thus, the T-cell responses detected at or after diagnosis may not reflect the pathogenic process leading to type 1 diabetes.
Division of Pediatrics and Diabetes Research Centre, Department of Molecular & Clinical Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden. maria.faresjo@imk.liu.se
Maria Karlsson
MK
Faresjö
Outi
O
Vaarala
Sophie
S
Thuswaldner
Jorma
J
Ilonen
Ari
A
Hinkkanen
Johnny
J
Ludvigsson
D000293:Adolescent; D001324:Autoantigens / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007328:Insulin / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D007328:Insulin; D007371:Interferon-gamma; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D005968:Glutamate Decarboxylase