Without depleting CD25+ cells, GAD113–132 and GAD265–284 responses were significantly stronger in subjects with diabetes. Although nearly every individual responded to at least one GAD65 epitope, most were seen in less than half of the subjects tested, suggesting that multiple epitopes are recommended for immune monitoring. Type 1 diabetes mellitus (T1D) is associated with antibody and T-cell responses to islet β-cell antigens. These responses lead to the selective destruction of pancreatic β cells, and a profound deficiency in insulin secretion.[1-3] Because T1D is strongly correlated with certain susceptible class

II haplotypes (including HLA-DQ2/DR3 and DQ8/DR4) and because Maraviroc cost CD4+ T cells have been shown to play a crucial role in animal models of T1D, it is widely held that the presentation of islet-derived epitopes by susceptible HLA class II proteins to pathogenic PD-0332991 nmr CD4+ T cells is a key component of the disease process. Previous studies have identified an array of diabetes-associated self-antigens including insulin, glutamic acid decarboxylase isoform 2 (GAD65), tyrosine phosphatase-like

protein, islet glucose-6-phosphatase catalytic subunit-related protein, the cation efflux transporter ZnT8 and, more recently, chromogranin.[4-6] Among these antigens, insulin and GAD65 have been the most widely studied. GAD65 was identified nearly

20 years ago as a β-cell antigen that reacted with sera from patients with T1D.[7] Subsequent selleck inhibitor studies have demonstrated that GAD65 is involved in pathogenesis for animal models of autoimmune diabetes.[8-10] In humans, GAD65 specific auto-antibodies are found in > 70% of patients with new-onset T1D[11, 12] and their presence is an established marker for predicting diabetes risk.[13-15] Several studies have observed CD4+ T-cell responses to epitopes within β-cell antigens in patients with diabetes or in diabetes-susceptible mice. Particularly in the non-obese diabetic (NOD) mouse, adoptive transfer of T cells specific for single epitopes has been sufficient to induce disease.[10, 16] For this reason, a number of human studies have attempted to monitor autoimmune responses or to differentiate between diabetic subjects and healthy controls by measuring CD4+ T-cell responses to one or a small number of epitopes within these antigens.[17] While successful in some settings, this limited approach may not be optimal to capture the dynamics of the disease process in human populations. We hypothesized that susceptible HLAs lead to the generation of diverse repertoires of diabetogenic T cells in humans and that individual subjects respond to subsets of these epitopes.