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Peptide Immunotherapies in Type 1 Diabetes: Lessons from Animal Models

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Abstract:

Insulin dependent diabetes mellitus (Type 1 diabetes, T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells by proinflammatory autoreactive T cells. In the past, several therapeutic approaches have been exploited by immunologists aiming to regulate the autoimmune response; this can occur by deleting lymphocyte subsets and/or re-establishing immune tolerance via activation of regulatory T cells. The use of broad immunosuppressive drugs was the first approach to be explored. Subsequently, antibody-based immunotherapies failed to discriminate between autoreactive versus non-autoimmune effectors. Antigen-based immunotherapy is a third approach developed to manipulate beta cell autoimmunity. This approach allows the selective targeting of disease-relevant T cells, while leaving the remainder of the immune system intact. Animal models have been successfully employed to prevent or treat T1D by injection of either the self proteins or peptides derived from them. Peptide immunotherapies have been mainly experimented in the NOD mouse spontaneous model of disease. In this review we therefore report the main approaches that rely on the use of peptides obtained from relevant autoantigens such as glutamic acid decarboxylase, isoform 65 (GAD65), insulin, proinsulin and islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP). Protective peptides have proven to be effective in treating or delaying the diabetic process. We also highlight the main difficulties encountered in extrapolating data to guide clinical translational investigations in humans.





Keywords: Animal models; CD4+; CD8+; Cyclosporine; HLA; Humoral immunity; Insulin dependent diabetes mellitus; Protective peptides; Type 1 diabetes; autoimmunity; diabetic syndrome; disease prevention; epitopes; form 65 (GAD65); glutamic acid decarboxylase; glycosuria; hyperglycemia; immunoregulatory T cells; insulin; islet cell antibodies (ICA); islet cell surface antibodies (ICSA); islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP); islets of Langherans; ketosis prone; lymphopenia; macrophages; major his-tocompatibility complex; pancreatectomy; pancreatic beta cells; peptide immunotherapy; proinflammatory autoreactive; proinsulin

Document Type: Research Article

DOI: https://doi.org/10.2174/092986711794480230

Publication date: 2011-02-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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