Prevention of type 1 diabetes: today and tomorrow.

Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Târgu Mureş Emergency County Clinical Hospital, 50Gheorghe Marinescu Str., Târgu Mureş, Romania.
Diabetes/Metabolism Research and Reviews (Impact Factor: 2.97). 10/2010; 26(8):602-5. DOI: 10.1002/dmrr.1138
Source: PubMed

ABSTRACT The aim of therapeutic interventions for type 1 diabetes is to suppress pathogenic autoreactivity and to preserve/restore beta-cell mass and function to physiologically sufficient levels to maintain good metabolic control. During the natural history of type 1 diabetes, several strategies have been applied at various stages in the form of primary, secondary or tertiary prevention approaches. Clinical trials using antigen-specific (e.g. DiaPep277, human glutamic acid decarboxylase 65 (GAD65)) or non-specific immune therapies (e.g. anti-CD3 monoclonal antibodies) have shown some benefit in the modulation of the autoimmune process and prevention of the insulin secretion loss in the short term after diagnosis of diabetes. A single long-term effective therapy has not been identified yet, and it is likely that in most cases a rationally designed combinatorial approach using immunotherapeutic methods coupled with islet regeneration or replacement will prove to be most effective.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called "Tregitopes") have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4(+) T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. In ex vivo studies of human T cells, peripheral blood mononuclear cells' (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopes ex vivo by Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management.
    Journal of Diabetes Research 01/2013; 2013:621693. · 3.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The integrity of the interactions and the 3D architecture among beta cell populations in pancreatic islets is critical for proper biosynthesis, storage and release of insulin. The aim of this study was to evaluate the effect on beta cells electrophysiological signalling of progressive lymphocytic islet cell infiltration (insulitis), by modelling the disruption of pancreatic islet's anatomy as consequence of insulitis and altered glucose concentration. METHODS: On the basis of histopathological images of murine islets from non-obese diabetic (NOD) mice, we simulated the electrophysiological dynamics of a 3D cluster of mouse beta cells via a stochastic model. Progressive damage was modelled at different glucose concentrations, representing the different glycaemic states in the autoimmune progression towards type 1 diabetes. RESULTS: At 31% of dead beta cells (normoglycaemia) and 69% (hyperglycaemia), the system appeared to be biologically robust to maintain regular Ca(2+) ions oscillations guaranteeing an effective insulin release. Simulations at 84%, 94% and 98% grades (severe hyperglycemia) showed that intracellular Calcium oscillations were absent. In such conditions insulin pulsatility is not expected to occur. CONCLUSIONS: Our results suggest that the islet tissue is biophysically robust enough to compensate high rates of beta cell loss. These predictions can be experimentally tested 'in vitro' quantifying space and time electrophysiological dynamics of animal islets kept at different glucose gradients. The model indicates the necessity of maintaining glycaemia within physiological levels as soon as possible after diabetes onset in order to avoid a dramatic interruption of Ca(2+) pulsatility and consequent drop of insulin release. Copyright © 2012 John Wiley & Sons, Ltd.
    Diabetes/Metabolism Research and Reviews 12/2012; · 2.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tregitopes are regulatory T cell epitopes derived from immunoglobulin G (IgG) that stimulate CD25(+) FoxP3(+) T cells to expand. In conjunction with these Tregs, Tregitopes can prevent, treat, and even cure autoimmune disease in mouse models, suppress allo-specific responses in murine transplant models, inhibit CD8(+) T cell responses to recombinant adeno-associated virus (AAV) gene transfer vectors, and induce adaptive Tregs in DO11.10 mice. In this review of recent Tregitope studies, we summarize their effects in vitro and describe recent comparisons between intravenous IgG (IVIG) and Tregitopes in standard in vivo immune tolerance models. Further investigations of the mechanism of action of Tregitopes in the preclinical models described here will lead to clinical trials where Tregitopes may have the potential to alter the treatment of autoimmune disease, transplantation, and allergy, and to improve the efficiency of gene and protein replacement therapies.
    Journal of Clinical Immunology 09/2012; · 3.38 Impact Factor