No abstract

Despite the understanding that type 1 diabetes pathogenesis is mediated by T-cells, detection of these rare lymphocytes remains largely elusive. Suitable T-cell assays are highly needed, since they could offer preclinical diagnoses and immune surrogate end points for clinical trials.

OBJECTIVE-Islet-reactive CD8ϩ T-cells play a key role in the pathogenesis of type 1 diabetes in the NOD mouse. The predominant T-cell specificities change over time, but whether similar shifts also occur after clinical diagnosis and insulin treatment in type 1 diabetic patients is unknown. RESEARCH DESIGN AND METHODS-We took advantage of a recently validated islet-specific CD8ϩ T-cell ␥-interferon enzyme-linked immunospot (ISL8Spot) assay to follow responses against preproinsulin (PPI), GAD, insulinoma-associated protein 2 (IA-2), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) epitopes in 15 HLA-A2 ϩ adult type 1 diabetic patients close to diagnosis and at a second time point 7-16 months later. RESULTS-CD8ϩ T-cell reactivities were less frequent at follow-up, as 28.6% of responses tested positive at type 1 diabetes diagnosis vs. 13.2% after a median of 11 months (P ϭ 0.003). While GAD and IA-2 autoantibody (aAb) titers were unchanged in 75% of cases, the fraction of patients responding to PPI and/or GAD epitopes by ISL8Spot decreased from 60 -67 to 20% (P Ͻ 0.02). The previously subdominant IA-2 206 -214 and IGRP [265][266][267][268][269][270][271][272][273] peptides were newly targeted, thus becoming the immunodominant epitopes. CONCLUSIONS-Shifts both in frequency and in immunodominance of CD8ϩ T-cell responses occur more rapidly than do changes in aAb titers. These different kinetics may suggest complementary clinical applications for T-cell and aAb measurements. Diabetes 57:1312-1320, 2008

OBJECTIVE -Incidence of type 1 diabetes is considered to be low in adults, but no study has been performed in Mediterranean countries.RESEARCH DESIGN AND METHODS -We extended the study base of the registry of the province of Turin, Italy, to subjects aged 30 -49 years in the period 1999 -2001 to estimate the incidences of type 1 and type 2 diabetes. Diagnosis of type 1 diabetes was based on permanent insulin treatment or a fasting C-peptide level Յ0.20 nmol/l or islet cell (ICA) or GAD (GADA) antibody positivities.RESULTS -We identified 1,135 case subjects with high completeness of ascertainment (99%), giving an incidence rate of 58.0 per 100,000 person-years (95% CI 54.7-61.5). The incidence of type 1 diabetes was 7.3 per 100,000 person-years (6.2-8.6), comparable with the rates in subjects aged 0 -14 and 15-29 years (10.3 [9.5-11.2] and 6.8 [6.3-7.4]). Male subjects had a higher risk than female subjects for both type 1 (rate ratio [RR] CONCLUSIONS -Risk of type 1 diabetes between age 30 and 49 years is similar to that found in the same area between age 15 and 29 years. Further studies are required to allow geographical comparisons of risks of both childhood and adulthood autoimmune diabetes, the latter being probably higher than previously believed.