Type 1 diabetes is a T-cell-mediated disease that is associated with loss of immunological tolerance to selfantigens. The mechanisms involved in maintenance of peripheral tolerance include a specialized subset of regulatory T-cells (Treg) within the CD4 ؉ CD25 ؉ T-cell population, but the function and phenotype of these cells in type 1 diabetes have not been investigated. We hypothesized that a deficiency in the CD4 ؉ CD25 ؉ Treg population or its function could contribute to the lack of self-tolerance evident in patients with type 1 diabetes. We show that although levels of CD4 ؉ CD25 ؉ T-cells are normal in patients with recent-onset adult type 1 diabetes, the ability of the Tregs in this population to suppress T-cell proliferation during in vitro cocultures is markedly reduced compared with control subjects (P ‫؍‬ 0.007). Moreover, in patients with type 1 diabetes, these cocultures display a more proinflammatory phenotype, with increased secretion of interferon-␥ (P ‫؍‬ 0.005) and decreased interleukin-10 production (P ‫؍‬ 0.03). These deficiencies may reflect a disturbance in the balance of the CD4 ؉ CD25 ؉ population, because in patients with type 1 diabetes, a higher proportion of these cells coexpress the early activation marker CD69 (P ‫؍‬ 0.007) and intracellular CTLA-4 (P ‫؍‬ 0.01). These data demonstrate deficiency in function of the CD4 ؉ CD25؉ Treg population that may influence the pathogenesis of type 1 diabetes. Diabetes 54:92-99, 2005

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Objective To describe and compare women and health care professionals' preferences for Down's Syndrome screening tests with different test characteristics. Design Cross sectional questionnaire based conjoint analysis study.Setting London teaching hospital.

Aims/hypothesis Islet antibody-negative first-degree relatives of type 1 diabetes patients have a very low risk of developing diabetes. We studied the balance between IFN-γ (proinflammatory) and IL-10 (regulatory) T cell responses in these participants. Methods Peripheral blood T cells from adult (18-50 years old, n=40) DRB1*0401-positive first-degree relatives negative for GAD and tyrosine phosphatase-like insulinoma antigen 2 (IA-2) antibodies were tested for IFN-γ and IL-10 responses in a sensitive cytokine enzyme-linked immunospot assay against a panel of seven peptide epitopes derived from IA-2 and proinsulin. Comparison was made with HLAmatched newly diagnosed type 1 diabetic patients (n=42) and healthy controls (n=39). Results First-degree relatives and newly diagnosed type 1 diabetic patients displayed a similar frequency of IFN-γ responses to the peptide panel and both were significantly greater than in healthy controls (relatives 9.6%, patients 11.8%, controls 4.0%, p=0.003). First-degree relatives and newly diagnosed type 1 diabetic patients also showed similar frequencies of IL-10 responses, which were significantly lower than in healthy controls (relatives 7.1%, patients 9.0%, controls 15.8%, p=0.003). However, individual IL-10 responses of first-degree relatives were similar in size to those in healthy controls and larger than those in newly diagnosed type 1 diabetic patients (relatives median 29 spot-forming cells/1×10 6 peripheral blood mononuclear cells, controls 33, patients 11, p=0.02). Conclusions/interpretation Taken together, these results suggest that antibody-negative first-degree relatives have a balance of proinflammatory and regulatory T cells, which is intermediate between that of newly diagnosed type 1 diabetic patients and healthy controls. This suggests that even a moderate regulatory response may be sufficient to prevent the development of clinical type 1 diabetes in genetically predisposed individuals.