Primary and secondary prevention of Type 1 diabetes

Skyler, Jay S.

doi:10.1111/dme.12100

Cited by 76 publications

(50 citation statements)

References 47 publications

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“…With the increasing incidence of T1D over the last two decades, especially in children less than 5 y of age (3), and the ability to predict diabetes development in individuals with two or more islet autoantibodies (4), diabetes prevention trials are underway (30). Antigen-specific therapy holds the potential for being able to safely and specifically induce tolerance to an administered self-antigen.…”

Section: Discussionmentioning

confidence: 99%

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Nakayama

McDaniel

Fitzgerald-Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA g7 , in an unfavorable position or register. Because of the similarities between IA g7 and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulinspecific therapies to prevent diabetes onset.T ype 1 diabetes (T1D), the autoimmune form of diabetes, results from T cell-mediated destruction of insulin-producing β-cells within pancreatic islets (1). The disease is dramatically increasing in incidence, doubling in the last two decades (2, 3), and now predictable with the measurement of antibodies directed against insulin and other proteins found in β-cells (4). Major efforts at disease prevention have been undertaken using preparations of insulin (s.c., oral, and intranasal) to induce tolerance and delay the onset of clinical symptoms (5-7). Measuring insulin-specific T-cell responses from the peripheral blood has been challenging but would allow for assessment of therapeutic response, which has been a major obstacle in these trials. In our study, we sought to detect peripheral T-cell responses to insulin in T1D patients and nondiabetic controls using a modified insulin B-chain peptide.Insulin is a major self-antigen for both T and B cells in murine and human T1D, with insulin B-chain amino acids 9-23 (B:9-23) being a key epitope presented by major histocompatibility complex class II (MHCII) molecules to CD4 T cells targeting pancreatic β-cells (8-10). There is strong evidence from the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes that the NOD MHCII molecule, IA g7 , is required for development of T1D and that pathogenic CD4 T cells recognize insulin B:9-23 presented in an unfavorable position or register (Reg3) in the IA g7 peptide binding groove (9, 11,...

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Section: Discussionmentioning

confidence: 99%

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Nakayama

McDaniel

Fitzgerald-Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…However, to date, none of several tested interventions has been successful in preventing type 1 diabetes in human beings [48,49]. Most of the studies have been conducted in relatives of people with type 1 diabetes, who have an increased risk of the disease.…”

Section: Immune Interventionmentioning

confidence: 99%

Hope vs hype: where are we in type 1 diabetes?

Skyler

2017

Diabetologia

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Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.

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“…A variety of other trials using a wide variety of agents such as omega 3 fatty acids, GAD, Vitamin D, and other are in progress to evaluate their role in prevention of diabetes (27). In patients with new onset type 1 diabetes, a variety of immunosuppressive agents have also been tried including steroids and immuran, cyclosporine, rituximab, and teplizumab.…”

Section: Preventionmentioning

confidence: 99%

“…In patients with new onset type 1 diabetes, a variety of immunosuppressive agents have also been tried including steroids and immuran, cyclosporine, rituximab, and teplizumab. These studies have demonstrated short-term preservation of insulin secretion (27,28). It is not clear that these therapies by themselves have a favorable risk: benefit ratio.…”

Section: Preventionmentioning

confidence: 99%

Type 1 diabetes: where are we in 2017?

Copenhaver

Hoffman

2017

Transl. Pediatr

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Type 1 diabetes mellitus is a chronic state of insulin deficiency which results from destruction of beta cells by the immune system. The long term microvascular and macrovascular complications can be devastating. Since the discovery of insulin almost 100 years ago new medical therapies have improved the long-term survival for people with type 1 diabetes. Each year we come closer to discovering a cure but much work still needs to be done to eliminate this disease.

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Primary and secondary prevention of Type 1 diabetes

Cited by 76 publications

References 47 publications

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Hope vs hype: where are we in type 1 diabetes?

Type 1 diabetes: where are we in 2017?

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