Insulin: a critical autoantigen and potential therapeutic agent in Type 1 diabetes

Pugliese, Alberto

doi:10.1586/1744666x.2.3.419

Cited by 5 publications

(4 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, what may ultimately be critical in developing robust long lasting tolerance is induction of autoantigen specific Tregs where low-dose IL-2 may help to increase their numbers. A clinical trial in patients with T1D, who by necessity immunize themselves with a key autoantigen, insulin [126], on a daily basis, present a unique opportunity to test this concept and may be relevant to other autoimmune diseases. Lastly, IL-2 exhibits poor pharmacokinetic with very short-half life in the blood, approximately 30 min.…”

Section: Discussionmentioning

confidence: 99%

Promoting Immune Regulation in Type 1 Diabetes Using Low-Dose Interleukin-2

et al. 2016

Self Cite

View full text Add to dashboard Cite

Dysregulation of the immune system contributes to the breakdown of immune regulation, leading to autoimmune diseases, such as type 1 diabetes (T1D). Current therapies for T1D include daily insulin, due to pancreatic β-cell destruction to maintain blood glucose levels, suppressive immunotherapy to decrease the symptoms associated with autoimmunity, and islet transplantation. Genetic risks for T1D have been linked to IL-2 and IL-2R signaling pathways that lead to the breakdown of self-tolerance mechanisms, primarily through altered regulatory T cell (Treg) function and homeostasis. In attempt to correct such deficits, therapeutic administration of IL-2 at low-doses has gained attention due to the capacity to boost Tregs without the unwanted stimulation of effector T cells. Preclinical and clinical studies utilizing low-dose IL-2 have shown promising results to expand Tregs due to their high selective sensitivity to respond to IL-2. These results suggest that low-dose IL-2 therapy represents a new class of immunotherapy for T1D by promoting immune regulation rather than broadly suppressing unwanted and beneficial immune responses.

show abstract

Section: Discussionmentioning

confidence: 99%

Promoting Immune Regulation in Type 1 Diabetes Using Low-Dose Interleukin-2

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…We and others have shown that this is the case for insulin. In man, insulin expression in the thymus is influenced by allelic variation and epigenetic regulation of the insulin gene [40, 41], noting that this has been identified as a susceptibility locus for T1D and insulin is a key autoantigen [42, 43]. We also showed that other T1D autoantigens, such as IA-2 and IGRP, exist in several spliced variants with different expression patterns in human pancreas and thymus, suggesting that self-tolerance may not be achievable to epitopes expressed only by the pancreas [44–47].…”

Section: Type 1 Diabetes: An Autoimmune Disease With Chronic Immune Dmentioning

confidence: 99%

The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation

2013

Self Cite

View full text Add to dashboard Cite

IL-2 plays a critical role in the normal function of the immune system. A trophic factor for lymphocytes, IL-2 is required for mounting and sustaining adaptive T cell responses; however, IL-2 is also critical for immune regulation via its effects on regulatory T cells (Treg cells). Over the years, we have contributed to the understanding of the biology of IL-2 and its signaling through the IL-2 receptor and helped define the key role played by IL-2 in Treg development and function. Our data show that Treg cells have a heightened sensitivity to IL-2, which may create a therapeutic window to promote immune regulation by selective stimulation of Treg cells. We are now developing new efforts to translate this knowledge to the clinical arena, through our focused interest in Type 1 diabetes as a prototypic autoimmune disease. Specifically, we aim at developing IL-2-based therapeutic regimens and incorporate means to enhance antigen-specific Treg responses, for improved and more selective regulation of islet autoimmunity. In parallel, we are pursuing studies in preclinical models of autoimmunity and transplantation to define critical factors for successful adoptive Treg therapy and develop clinically applicable therapeutic protocols.

show abstract

“…Alternative splicing of Deaf1 may be caused by inflammation, which in turn impairs expression of the eukaryotic translation initiation factor 4 gamma 3 (Eif4g3) [43]. These studies illustrate molecular events that may result in lower expression of self-molecules (e.g., insulin, an autoantigen in T1D) [63] and impaired induction of peripheral tolerance at a site that is believed to be key to the regulation and activation of islet autoimmune responses, the pancreatic lymph node. nPOD also supported studies that provided a more in-depth phenotypic analysis of cells that express self-molecules in peripheral lymphoid tissues, in particular extra-thymic Aire -expressing cells [64] that are now known to represent a bone marrow-derived, distinct phenotype with similarities to dendritic cells [46•].…”

Section: Introductionmentioning

confidence: 99%

New Insight on Human Type 1 Diabetes Biology: nPOD and nPOD-Transplantation

et al. 2014

Self Cite

View full text Add to dashboard Cite

The Juvenile Diabetes Research Foundation (JDRF) Network for Pancreatic Organ Donors with Diabetes (JDRF nPOD) was established to obtain human pancreata and other tissues from organ donors with type 1 diabetes (T1D) in support of research focused on disease pathogenesis. Since 2007, nPOD has recovered tissues from over 100 T1D donors and distributed specimens to approximately 130 projects led by investigators worldwide. More recently, nPOD established a programmatic expansion that further links the transplantation world to nPOD, nPOD-Transplantation; this effort is pioneering novel approaches to extend the study of islet autoimmunity to the transplanted pancreas and to consent patients for postmortem organ donation directed towards diabetes research. Finally, nPOD actively fosters and coordinates collaborative research among nPOD investigators, with the formation of working groups and the application of team science approaches. Exciting findings are emerging from the collective work of nPOD investigators, which covers multiple aspects of islet autoimmunity and beta cell biology.

show abstract

Insulin: a critical autoantigen and potential therapeutic agent in Type 1 diabetes

Cited by 5 publications

References 104 publications

Promoting Immune Regulation in Type 1 Diabetes Using Low-Dose Interleukin-2

Promoting Immune Regulation in Type 1 Diabetes Using Low-Dose Interleukin-2

The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation

New Insight on Human Type 1 Diabetes Biology: nPOD and nPOD-Transplantation

Contact Info

Product

Resources

About