What is the role of autoimmunity in type 1 diabetes? A clinical perspective

Donath, Marc Y.; Hess, Christoph; Palmer, Ed

doi:10.1007/s00125-013-3153-0

Cited by 37 publications

(39 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, although a monotherapy with anti-TNF-a is an established successful therapy in a number of autoimmune diseases (15)(16)(17), anti-TNF-a is not effective in T1D treatment (18)(19)(20)(21)(22)(23). Anti-TNF-a neutralizes TNF-a, produced by the immune cells infiltrating the target organ during the inflammatory process (11,14,15,45), and the combination of anti-TNF-a with anti-TCR also prevents the release of IL-1b, the other critical proinflammatory cytokine for the disease process (3), from the activated T cells (25).…”

Section: Discussionmentioning

confidence: 99%

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

et al. 2015

View full text Add to dashboard Cite

Anti–tumor necrosis factor-α (TNF-α) therapy (5 mg/kg body weight), alone or combined with the T-cell–specific antibody anti–T-cell receptor (TCR) (0.5 mg/kg body weight), was performed over 5 days immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm rat, an animal model of human type 1 diabetes. Only combination therapy starting at blood glucose concentrations below 15 mmol/L restored normoglycemia and normalized C-peptide. Increased β-cell proliferation and reduced apoptosis led to a restoration of β-cell mass along with an immune cell infiltration–free pancreas 60 days after the end of therapy. This combination of two antibodies, anti-TCR/CD3, as a cornerstone compound in anti–T-cell therapy, and anti–TNF-α, as the most prominent and effective therapeutic antibody in suppressing TNF-α action in many autoimmune diseases, was able to reverse the diabetic metabolic state. With increasing blood glucose concentrations during the disease progression, however, the proapoptotic pressure on the residual β-cell mass increased, ultimately reaching a point where the reservoir of the surviving β-cells was insufficient to allow a restoration of normal β-cell mass through regeneration. The present results may open a therapeutic window for reversal of diabetic hyperglycemia in patients, worthwhile of being tested in clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Although predicted, these CD4 + T cells have never been isolated from human islets, leaving a crucial piece missing from the chain of autoimmune causation in T1D. This gap in our knowledge has led some to question about the autoimmune basis of human T1D (18,19).…”

Section: Type 1 Diabetes (T1d) Is An Autoimmune Disease Caused By Thementioning

confidence: 99%

Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer–Restricted CD4+ T Cells Infiltrate Islets in Type 1 Diabetes

et al. 2014

View full text Add to dashboard Cite

Type 1 diabetes (T1D) develops when insulin-secreting b-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize b-cell-derived antigens remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These longstanding observations implicate CD4 + T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human b-cells, we isolated and characterized 53 CD4 + T-cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of which encoded proinsulin-specific T-cell receptors. On an individual clone basis, 14 of 53 CD4 + T-cell clones (26%) recognized 6 distinct but overlapping epitopes in the C-peptide of proinsulin. These clones recognized C-peptide epitopes presented by HLA-DQ8 and, notably, HLA-DQ8 transdimers that form in HLA-DQ2/-DQ8 heterozygous individuals. Responses to these epitopes were detected in the peripheral blood mononuclear cells of some people with recent-onset T1D but not in HLAmatched control subjects. Hence, proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4 + T cells are strongly implicated in the autoimmune pathogenesis of human T1D.Type 1 diabetes (T1D) is an autoimmune disease caused by the CD4 + and CD8 + T-cell-mediated destruction of pancreatic insulin-producing b-cells (1). b-Cell destruction leads to primary insulin deficiency, which is treated by exogenous insulin therapy, and currently there is no cure. The pathogenesis of T1D has been well characterized using the NOD mouse model, but the immune basis of T1D in humans is less clear.Genetic association studies have provided powerful insights into the etiology of human T1D (2,3). The HLA class II region has the strongest impact on risk of T1D. Some HLA alleles-DQB1*06:02 for example-dominantly protect against T1D (4). In contrast, of all alleles, HLA-DQ2

show abstract

“…Some of the measures that have been tested in human trials have been successfully used in the treatment of other autoimmune diseases such as rheumatoid arthritis, while others have been based on tolerance induction by delivering b-cell autoantigens per os, intranasally or subcutaneously. None of them has provided any clear long-term beneficial effect on the preservation of b-cell function, even though some promising effects have been observed in certain subgroups of patients [70,71]. Only one large-scale primary prevention trial has been initiated.…”

Section: Current Status Of Preventive Strategies For T1dmentioning

confidence: 95%

Developing a vaccine for Type 1 diabetes through targeting enteroviral infections

Hyöty¹,

Knip²

2014

Expert Review of Vaccines

View full text Add to dashboard Cite

Type 1 diabetes (T1D) is a chronic disease caused by the destruction of insulin producing β-cells in the pancreas. Studies carried out during the past decades have implied that enteroviruses could be an important causative agent. These findings have generated efforts aiming at developing vaccines against these viruses and testing their efficacy against T1D in clinical trials. Extensive work has been carried out to define the serotype of enteroviruses which are linked to T1D and which should be included in the vaccine, and experimental vaccines have been shown to be effective and safe in mouse models. Large-scale studies are currently in progress to increase the confidence in the scientific concept of the enterovirus-diabetes association, paralleling the efforts aimed at starting the clinical development of the vaccine. This review summarizes recent progress in this field and the scenarios regarding this development process.

show abstract

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

Cited by 37 publications

References 24 publications

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer–Restricted CD4+ T Cells Infiltrate Islets in Type 1 Diabetes

Developing a vaccine for Type 1 diabetes through targeting enteroviral infections

Contact Info

Product

Resources

About