OBJECTIVE There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes. RESEARCH DESIGN AND METHODS Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial–Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA+). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA+). RESULTS In both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes. CONCLUSIONS The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.

More than 71,000 relatives of type 1 diabetic patients have been screened for cytoplasmic islet cell antibodies (ICAs), GAD65 autoantibodies (GAAs), and ICA512 autoantibodies (ICA512AAs). Among those 71,148 relatives, 2,448 were cytoplasmic ICA1, and the remainder were ICA2. Of the ICA1 group, 1,229 (50.2%) were positive for GAAs and/or ICA512AAs. Among ICA2 relatives, 1,897 (2.76%) were positive for GAAs and/or ICA512AAs. Given the large number of relatives positive for cytoplasmic ICA and negative for “biochemically” determined autoantibodies, and the converse, we analyzed the proportion of ICA1 relatives found eligible to participate in the intervention phase of Diabetes Prevention Trial2Type 1 (DPT-1). To be eligible for the parenteral insulin DPT-1 trial, a relative had to have first-phase insulin secretion below the 1st percentile of cut-points (for parents) or below the 10th percentile (for siblings and offspring). To be eligible for the oral insulin trial, a relative had to have first-phase insulin secretion above cut-points (>1st percentile for parents, >10th percentile for siblings/offspring) and be positive for anti-insulin autoantibodies. For both trials, DQB1*0602 was an exclusion criteria, cytoplasmic ICA positivity had to be confirmed, and an oral glucose tolerance test had to result in nondiabetic levels. Of 572 relatives found to be eligible for trial entry, 442 (77.3%) were positive for GAAs and/or ICA512AAs, although overall only 50.2% of ICA1 relatives were positive for GAAs and/or ICA512AAs. The positive predictive value for trial eligibility for ICA1 relatives with GAAs or ICA512AAs who completed staging was 51.0%. In contrast, only 11.9% of ICA1 but GAA2 and ICA512AA2 relatives were found to be eligible by DPT criteria for trial entry. Positivity for biochemically determined autoantibodies among cytoplasmic antibody–positive relatives is associated with eligibility for the DPT-1 study. Diabetes 50:1735–1740, 2001

Nature 391, 177–181 (1998) In this Letter, we reported that invariant Vα24JαQ T cells from monozygotic diabetic twins/triplets were reduced in number and produced only interferon-γ on appropriate stimulation, whereas those cloned from at-risk non-diabetic twins/triplets and controls produced both interferon-γ and interleukin(IL)-4.

Nature 396, 55±57 (1998) .................................................................................................................................. Figure 3 of this Letter wrongly shows all cobalt sites as yellow ®lled circles, indicating that they lie on the same c ˆ 0 level, whereas the two lower sites in the ®gure were intended to be open circles, indicating cobalt sites on the c ˆ 1=2 level. A corrected version of the ®gure can be found on Nature's website.

Proliferation of human CD4+ alphabeta T cells expressing a natural killer cell activating receptor (NKAR) has been shown to be enhanced, particularly in response to low doses of antigen, if the target cells present appropriate human class I major histocompatibility complex (MHC) molecules. Here, we show that NKAR also enhance proliferation and killing of target cells by subsets of CD8+ alphabeta and CD8+ gammadelta T cells, as well as by NK cells. Strikingly, interferon gamma secretion from all of these types of lymphocytes was markedly increased by interaction of the NKAR with their MHC class I ligands, independently of enhancement of proliferation. Thus, the recognition of class I MHC molecules by NKAR on both T cells and NK cells may provide a regulatory mechanism that affects immune responses through the secretion of interferon gamma and possibly other cytokines. It represents a signal for cytokine secretion alternative and/or augmentative to that through the T cell receptor.

Type 1 diabetes in humans is a chronic autoimmune disease. Present treatments are difficult and not always effective. Because of this, a number of therapies aimed at altering the immune response have been tried in patients with a new onset of diabetes. Although some of these therapies have been promising, they are limited by the near-total β-cell destruction that has already occurred at the lime of onset of clinical diabetes. Because of this limitation, recent efforts in immunotherapy have focused on an earlier, prediabetic stage, in which there are more functioning β cells remaining. After a number of small controlled trials and a few pilot trials, investigators around the world are now collaborating on three different multicenter, randomized, controlled trials of intervention for Type 1 diabetes: the Diabetes Prevention Trial Type 1 (DPT-1), a National Institutes of Health-sponsored trial in the United States that will study the effects of parenteral and oral insulin in high-risk relatives; the European Nicotinamide Diabetes intervention Trial (ENDIT), a Canadian-European trial that will give nicotinamide to islet-cell antibody-positive relatives; and a Finnish-Canadian trial that will compare high-risk newborns fed cow-based formula with those receiving a non-cow-based formula for 6 months.

Previous studies suggest that after 6 years of discordance, identical twin pairs rarely become concordant for type I diabetes. With up to 39 years of follow-up from the onset of diabetes in the index twin, we determined how many discordant twins have evidence of beta-cell autoimmunity and how many develop overt diabetes. We longitudinally followed 23 pairs of identical twins (or triplets) that were selected from a total group of 30 pairs because they were discordant for type I diabetes when first ascertained. Seven developed diabetes after 3, 3, 7, 8, 9, 31 and 36 years of discordance. By survival analysis, the concordance after 10 years from the onset of diabetes in the index twin was estimated as 23% (95% confidence interval, 5-40%), increasing to 38% (95% confidence interval, 8-69%) after 31 years. Among 16 twins remaining nondiabetic at last follow-up (8-39 years of discordance), 12 were assessed with serial intravenous glucose tolerance tests and a total of 407 measurements by radioassay of antibodies against three defined autoantigens (glutamic acid decarboxylase, insulin, and the recently cloned molecule ICA512). Two-thirds (8 of 12) had evidence of beta-cell autoimmunity (persistently positive autoantibody levels) and/or first-phase insulin release less than the 1st percentile of control subjects. In summary, identical twins may develop diabetes after a prolonged period of discordance and approximately two-thirds of long-term discordant twins have evidence of persistent beta-cell autoimmunity and/or beta-cell damage. The concordance for beta-cell autoimmunity, therefore, is much higher than for overt diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

From studies of non-organ specific autoimmune diseases such as Lupus Erythematosus the concept has developed that autoimmunity is characterized by marked variation over time reflected by clinical remission and exacerbation. Our family studies of the development of Type I diabetes is providing us with a very different picture of the autoimmunity associated with Type I diabetes. In addition studies of NOD mice indicate that the Mendelian inheritance of a series of necessary but not sufficient diabetes associated alleles (H-2 NOD, theta linked, and the autosomal recessive gene determining anti-polar antibodies) create diabetes susceptibility. We will review our studies indicating that Type I diabetes is an autoimmune process in which there is remarkable quantitative stability of autoantibody levels amongst prediabetics (at times extending to more than a decade).