PERSISTENT ACTIVATION OF CD8(-CELLS CHARACTERIZES PREDIABETIC TWINS()T)

OBJECTIVE - Elevated circulating levels of activated CD3(+) T-cells ar e characteristic of type I diabetes at diagnosis, and activated CD8(+) (cytotoxic/suppressor) T-cells predominate in the islet infiltrate. T he aim of this study was to examine the peripheral blood of prediabeti c and nondiabetic identical twins of patients with type I diabetes for the presence of activated CD8(+) T-cells and by comparing these group s, analyze the relationship of such cells to the development of the di sease. RESEARCH DESIGN AND METHODS - In a 10-year prospective study, b lood T-cell subsets (CD3(+) total T-cells, CD4(+) helper/inducer, and CD8(+) cytotoxic/suppressor) were analyzed for evidence of activation (cell surface expression of HLA-DR, CD25) in 18 identical twins of pat ients with type I diabetes, 8 of whom became diabetic (prediabetic twi ns), while 10 remained nondiabetic after at least 8 years of follow-up and are now at low risk for type I diabetes. Fifteen healthy individu als were studied as control subjects. RESULTS - At the beginning and d uring the study, percentage levels of activated CD3(+) HLA-DR(+) T-cel ls were significantly elevated in prediabetic and low-risk mins compar ed with control subjects (P < 0.005) but remained high only in prediab etic twins (P < 0.005). Both prediabetic and low-risk twins had elevat ed levels of HLA-DR(+) CD4(+) T helper cells compared with control sub jects throughout the study (P < 0.001), and these remained high in bot h (P < 0.001 and P < 0.05, respectively). Only prediabetic twins had e levated levels of HLA-DR(+) CD8(+) T-cells during the study These were significantly higher than in control subjects (P < 0.005) and low-ris k twins (P < 0.05) and remained persistently elevated to diagnosis (P < 0.001). Abnormally elevated levels of HLA-DR(+) CD8(+) T-cells in mi ns indicate a 50% risk of progression to type I diabetes by life-table analysis (P = 0.01), with a positive predictive value of 100%, sensit ivity of 50%, and specificity of 100%. Elevated CD25(+) T-cell levels in prediabetic and low-risk twins were less marked and less able to di scriminate between the min groups. CONCLUSIONS - These results demonst rate that prediabetes is characterized by persistent elevation of HLA- DR(+) CD8(+) T-cells with the same cytotoxic phenotype as cells predom inating in the islet at diagnosis, suggesting that the circulating cel ls may have a role in the pathogenesis of islet damage.