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: 3.55). 11/2010; 26(8):602-5. DOI: 10.1002/dmrr.1138
Source: PubMed


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.

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Available from: Simona Cernea, Mar 30, 2015
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    • "Reducing islet cell destruction and preserving islet cell function are the goals of therapies intended to cure T1D. Proposed treatments with anti-CD3 monoclonal antibodies (mAbs) such as Teplizumab, which induce Tregs, have shown some efficacy, but the mechanism of Treg induction is elusive and the effect appears to be either brief and/or requires treatment very early in T1D disease [37]. The critical period for intervention is at the onset of diabetes, when Tregs can protect islet cell mass [30]. "
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    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.
    Full-text · Article · Apr 2013 · Journal of Diabetes Research
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    • "Emerging approaches to autoimmune disease treatment currently involve induction of Tregs using monoclonal antibodies (mAbs) such as anti-CD3 (Teplizumab, Macrogenics, Otelixizumab, and Tolerx), which induce Treg cells. Anti-CD3 treatment has shown some efficacy in human studies, but the mechanism of Treg induction is elusive and the effect appears to be short lasting [49, 50]. Antigen specificity and localized immunosuppressive effects are believed to be advantages of the Tregitope approach that might reduce side effects (such as infections) associated with more broadly suppressive treatments. "
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    ABSTRACT: The induction of immunologic tolerance is an important clinical goal in autoimmunity. CD4(+) regulatory T (Treg) cells, defined by the expression of the transcription factor forkhead box P3 (FoxP3), play a central role in the control of autoimmune responses. Quantitative and qualitative defects of Tregs have been postulated to contribute to failed immune regulation in multiple sclerosis (MS) and other autoimmune diseases. This paper highlights the potential uses of T regulatory cell epitopes (Tregitopes), natural Treg epitopes found to be contained in human immunoglobulins, as immunomodulating agents in MS. Tregitopes expand Treg cells and induce "adaptive Tregs" resulting in immunosuppression and, therefore, are being considered as a potential therapy for autoimmune diseases. We will compare Tregitopes versus intravenous immunoglobulin (IVIg) in the treatment of EAE with emphasis on the potential applications of Tregitope for the treatment of MS.
    Full-text · Article · Sep 2011 · Neurology Research International
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    ABSTRACT: Douglas M Ruden1, Xiangyi Lu21Wayne State University, Department of Obstetrics and Gynecology, C. S. Mott Center for Human Growth and Development, Institute of Environmental Health Sciences, Detroit, MI, USA; 2Institute of Environmental Health Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USAAbstract: According to the International Diabetes Federation (IDF), 190 million people worldwide suffer from diabetes, and this number is estimated to double by the year 2025. Diabetes is especially prominent in the elderly population because the IDF indicates age above 45 years as a major risk factor for diabetes. The most common trials for controlling diabetes focus on tighter glucose control as a means to reduce the long-term complications. However, whether tight blood sugar control or other dietary or pharmaceutical interventions in the elderly are more appropriate is not known. Major changes have taken place in our diet over the past 10,000 years since the beginning of the Agricultural Revolution, but our genes have not changed. Furthermore, the large numbers of diabetic elderly in the population are a recent phenomenon, because those with diabetes have historically died young. Genetically speaking, humans today live in a nutritional environment that differs from that for which our genetic constitution was selected. For example a high omega-6/omega-3 ratio, found in today’s Western diets, promotes the pathogenesis of many chronic diseases, including cardiovascular disease and diabetes. Knowing who is at risk would be useful if it meant that one could avoid the environmental triggers that convert susceptibility to disease. The prospect of targeting specific dietary treatments at the elderly, who are predicted to gain the most therapeutic benefits, clearly has important clinical and economic consequences. In this review, we will discuss modern molecular genetic and epidemiological techniques which are now, or soon will be, made available by inexpensive whole-genome sequencing and other whole genome approaches to treat the elderly diabetic population.Keywords: diabetes, elderly diabetic population, DNA, genome sequencing
    Full-text · Article · Jan 2011 · Nutrition and Dietary Supplements
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