Th1-like dominance in high-risk first-degree relatives of Type I diabetic patients

Aims/hypothesis. The humoral part of the immune system, including autoantibodies, is known to predict manifest Type I (insulin-dependent) diabetes mellitus in first-degree relatives but the cell-mediated immune process preceding the manifest disease still is not known. The aim of this investigation was to estimate the immunological balance of Th-like lymphocytes (Th1/Th2) in high-risk first-degree relatives of Type I diabetic children. Methods. Peripheral blood mononuclear cells (PBMC) from 21 healthy high-risk first-degree relatives (ICA greater than or equal to 20) were examined and compared with the response seen in PBMC from children with newly diagnosed Type I diabetes and healthy control subjects of similar age, sex and HLA-type. Expression of interteukin-4 (IL-4) and interferon-gamma (IFN-gamma) mRNA were determined by RT-PCR and as protein by ELISPOT after stimulation with specific epitopes of GAD(65) (a.a. 247-279, 509-528, 524-543), bovine serum albumin, the ABBOS peptide (a.a. 152-169) and insulin. Results. High-risk relatives had a high ratio of IFN-gamma:IL-4 compared with both diabetic children (p = 0.0005) and healthy control subjects (p = 0.004). Production of IFN-gamma seen in high-risk relatives was negatively correlated to production of GADA (r = -0.44, p = 0.05). The high concentration of IFN-gamma from high-risk relatives, decreased after stimulation with peptides of GAD(65), the ABBOS peptide, BSA and insulin. Increased secretion of IL-4 was observed after stimulation with two peptides of GAD(65) (a.a. 509-528 and 524-543), the ABBOS peptide and insulin. Conclusion/interpretation. Overwhelming production of IFN-gamma seen in peripheral blood mononuclear cells from high-risk first-degree relatives of children with Type I diabetes suggests a Th1-like immune deviation in the prediabetic phase.