Insulin as a Primary Autoantigen for Type 1A Diabetes

Jasinski, Jean; Eisenbarth, George S.

doi:10.1080/17402520500078204

Cited by 42 publications

(27 citation statements)

References 56 publications

(69 reference statements)

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“…Under more physiological conditions of limited frequencies of β-cell-reactive T cells, low numbers of highly diabetogenic CD4 Consistent with the concept that proinsulin is a major self-Ag and primary target during the early stages of T1D development [78][79][80], low-dosedelivery of whole proinsulin to + DCs in prediabetic NOD mice interfered with the progression towards overt diabetes; 50% of mice that received 4 consecutive injections of 1 µg anti-DECproinsulin mAbs at 2 months of age maintained normoglycemia until the end of the observation period at 6 month of age [63]. In contrast, 90% of NOD mice injected with equivalent amounts of isotype control Ab, or left untreated, had progressed towards overt autoimmune diabetes.…”

Section: Foxp3mentioning

confidence: 88%

Targeted Antigen Delivery to DEC-205⁺Dendritic Cells for Tolerogenic Vaccination

Petzold¹,

Schallenberg²,

Stern³

et al. 2012

Rev Diabet Stud

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■ AbstractDendritic cells (DCs) and Foxp3-expressing CD4 + regulatory T (Treg) cells play non-redundant roles in the maintenance of peripheral tolerance to self-antigens, thereby preventing fatal autoimmunity. A common hallmark of intra-and extrathymic Treg cell lineage commitment is the induction of Foxp3 expression as a consequence of appropriate T cell receptor engagement with MHC class II:agonist ligand. It has now become increasingly clear that agonist ligand presentation by immature DCs in the steady state induces T cell tolerance by both recessive and dominant mechanisms, rather than promoting productive T helper cell responses. In this context, the ability of steady-state DCs to promote the extrathymic conversion of initially naïve CD4 + Foxp3 -T cells into Foxp3 + Treg cells is of particular interest as it provides novel perspectives to enhance antigen-specific Treg cell function in clinical settings of unwanted immunity, such as β-cell autoimmunity.

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Section: Foxp3mentioning

confidence: 88%

Targeted Antigen Delivery to DEC-205⁺Dendritic Cells for Tolerogenic Vaccination

Petzold¹,

Schallenberg²,

Stern³

et al. 2012

Rev Diabet Stud

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“…Antigenic specificities of intrapancreatic T cells have been mainly defined in the NOD mouse by studies showing that the initial challenge is driven by insulin-specific T cell responses (3,4), later spreading to GAD and other islet-related autoantigens (5,6). In contrast, the T cell targets of human T1D have been identified only from the analysis of peripheral T cells, mostly because of the limited availability of human pancreatic tissue.…”

Section: T Ype 1 Diabetes (T1d) Is An Autoimmune Disease Defined By Tmentioning

confidence: 99%

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Codina-Busqueta

Scholz

Torres

et al. 2011

The Journal of Immunology

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Autoreactive T cells, responsible for the destruction of pancreatic β cells in type 1 diabetes, are known to have a skewed TCR repertoire in the NOD mouse. To define the autoreactive T cell repertoire in human diabetes, we searched for intraislet monoclonal expansions from a recent onset in human pancreas to then trace them down to the patient’s peripheral blood and spleen. Islet infiltration was diverse, but five monoclonal TCR β-chain variable expansions were detected for Vβ1, Vβ7, Vβ11, Vβ17, and Vβ22 families. To identify any sequence bias in the TCRs from intrapancreatic T cells, we analyzed 139 different CDR3 sequences. We observed amino acid preferences in the NDN region that suggested a skewed TCR repertoire within infiltrating T cells. The monoclonal expanded TCR sequences contained amino acid combinations that fit the observed bias. Using these CDR3 sequences as a marker, we traced some of these expansions in the spleen. There, we identified a Vβ22 monoclonal expansion with identical CDR3 sequence to that found in the islets within a polyclonal TCR β-chain variable repertoire. The same Vβ22 TCR was detected in the patient’s PBMCs, making a cross talk between the pancreas and spleen that was reflected in peripheral blood evident. No other pancreatic monoclonal expansions were found in peripheral blood or the spleen, suggesting that the Vβ22 clone may have expanded or accumulated in situ by an autoantigen present in both the spleen and pancreas. Thus, the patient’s spleen might be contributing to disease perpetuation by expanding or retaining some autoreactive T cells.

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“…Insulin and glutamic acid decarboxylase 65 (GAD 65 ) are major auto-antigens in type 1 diabetes [23,24] and have been tested in immunomodulation experiments [25]. Data from studies of the spontaneously diabetic NOD mouse have indicated that GAD 65 prevents type 1 diabetes [26,27].…”

Section: Introductionmentioning

confidence: 99%

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

et al. 2010

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Aims/hypothesis The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD 65 (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. Methods Seventy children and adolescents aged 10-18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 μg of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. Results One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GADalum group fasting C-peptide was 0.332±0.032 nmol/l at day 1 and 0.215 ± 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354± 0.039 and 0.184±0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GADalum group than in the placebo-treated group after 4 years.

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Insulin as a Primary Autoantigen for Type 1A Diabetes

Cited by 42 publications

References 56 publications

Targeted Antigen Delivery to DEC-205⁺Dendritic Cells for Tolerogenic Vaccination

Targeted Antigen Delivery to DEC-205⁺Dendritic Cells for Tolerogenic Vaccination

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

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Insulin as a Primary Autoantigen for Type 1A Diabetes

Cited by 42 publications

References 56 publications

Targeted Antigen Delivery to DEC-205+Dendritic Cells for Tolerogenic Vaccination

Targeted Antigen Delivery to DEC-205+Dendritic Cells for Tolerogenic Vaccination

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

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Product

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Targeted Antigen Delivery to DEC-205⁺Dendritic Cells for Tolerogenic Vaccination

Targeted Antigen Delivery to DEC-205⁺Dendritic Cells for Tolerogenic Vaccination