Recognition of HLA Class I–Restricted β-Cell Epitopes in Type 1 Diabetes

Ouyang, Qing; Standifer, Nathan; Qin, Huilian; Gottlieb, Peter A.; Verchere, C. Bruce; Nepom, Gerald T.; Tan, Rusung; Panagiotopoulos, Constadina

doi:10.2337/db06-0065

Cited by 97 publications

(80 citation statements)

References 32 publications

(27 reference statements)

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“…ϩ T-cells in the peripheral blood of patients (23)(24)(25)(26)(27)(28). These observations suggest the possibility that peptide-based predictive, diagnostic, monitoring, and therapeutic strategies targeting islet-reactive CD8 ϩ T-cells may be feasible.…”

mentioning

confidence: 88%

“…Thus, several criteria have been developed to select candidate peptides for these investigations. These include predicted or experimental binding to an HLA molecule of interest (23)(24)(25)(26)(27)(28)41), predicted or experimental evidence for proteasomal cleavage at the peptide's COOH-terminus (26 -28,41), and immunogenicity when administered to an HLA transgenic mouse (23,41). These criteria, often used in combination, have been helpful in allowing the identification of candidate peptides that were subsequently shown to be recognized by peripheral T-cells of type 1 diabetic patients directly ex vivo.…”

Section: Cd8mentioning

confidence: 99%

“…ϩ T-cells reactive to several islet antigens, including insulin and IGRP, have been detected in the peripheral blood of type 1 diabetic patients directly ex vivo (23)(24)(25)(26)(27)(28). The finite, and often small, amount of blood available from subjects requires investigators to limit the number of peptides that can be examined for T-cell reactivity.…”

Section: Cd8mentioning

confidence: 99%

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In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

et al. 2007

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OBJECTIVE—CD8+ T-cells specific for islet antigens are essential for the development of type 1 diabetes in the NOD mouse model of the disease. Such T-cells can also be detected in the blood of type 1 diabetic patients, suggesting their importance in the pathogenesis of the human disease as well. The development of peptide-based therapeutic reagents that target islet-reactive CD8+ T-cells will require the identification of disease-relevant epitopes. RESEARCH DESIGN AND METHODS—We used islet-infiltrating CD8+ T-cells from HLA-A*0201 transgenic NOD mice in an interferon-γ enzyme-linked immunospot assay to identify autoantigenic peptides targeted during the spontaneous development of disease. We concentrated on insulin (Ins), which is a key target of the autoimmune response in NOD mice and patients alike. RESULTS—We found that HLA-A*0201-restricted T-cells isolated from the islets of the transgenic mice were specific for Ins1 L3–11, Ins1 B5–14, and Ins1/2 A2–10. Insulin-reactive T-cells were present in the islets of mice as young as 5 weeks of age, suggesting an important function for these specificities early in the pathogenic process. Although there was individual variation in peptide reactivity, Ins1 B5–14 and Ins1/2 A2–10 were the immunodominant epitopes. Notably, in vivo cytotoxicity to cells bearing these peptides was observed, further confirming them as important targets of the pathogenic process. CONCLUSIONS—The human versions of B5–14 and A2–10, differing from the murine peptides by only a single residue, represent excellent candidates to explore as CD8+ T-cell targets in HLA-A*0201–positive type 1 diabetic patients.

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mentioning

confidence: 88%

Section: Cd8mentioning

confidence: 99%

Section: Cd8mentioning

confidence: 99%

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In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

et al. 2007

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“…While the decreasing proinsulin-specific responses and the increasing of IGRP [265][266][267][268][269][270][271][272][273] reactivity are reminiscent of NOD mouse data (6), the finding of a similar phenomenon for GAD and IA-2 is unparalleled. This is not surprising, since GAD and IA-2 are thought to be important target Ags in human type 1 diabetes (15,17,26,(37)(38)(39) but not in the NOD mouse (40 -43). Consideration of additional epitopes poorly recognized at type 1 diabetes onset (17,18) may reveal further specificities becoming immunodominant at later time points.…”

Section: Cd8mentioning

confidence: 99%

“…Their mean age at diagnosis was 27.6 Ϯ 8.4 years, and their median type 1 diabetes duration at the time of the first blood draw was 13 days (2-180). Fifteen age-matched healthy control subjects (mean age 28.8 Ϯ 5.9) were also tested twice within a median follow-up period of 14 months (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Section: Most Cd8mentioning

confidence: 99%

The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment

et al. 2008

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OBJECTIVE-Islet-reactive CD8ϩ T-cells play a key role in the pathogenesis of type 1 diabetes in the NOD mouse. The predominant T-cell specificities change over time, but whether similar shifts also occur after clinical diagnosis and insulin treatment in type 1 diabetic patients is unknown. RESEARCH DESIGN AND METHODS-We took advantage of a recently validated islet-specific CD8ϩ T-cell ␥-interferon enzyme-linked immunospot (ISL8Spot) assay to follow responses against preproinsulin (PPI), GAD, insulinoma-associated protein 2 (IA-2), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) epitopes in 15 HLA-A2 ϩ adult type 1 diabetic patients close to diagnosis and at a second time point 7-16 months later. RESULTS-CD8ϩ T-cell reactivities were less frequent at follow-up, as 28.6% of responses tested positive at type 1 diabetes diagnosis vs. 13.2% after a median of 11 months (P ϭ 0.003). While GAD and IA-2 autoantibody (aAb) titers were unchanged in 75% of cases, the fraction of patients responding to PPI and/or GAD epitopes by ISL8Spot decreased from 60 -67 to 20% (P Ͻ 0.02). The previously subdominant IA-2 206 -214 and IGRP [265][266][267][268][269][270][271][272][273] peptides were newly targeted, thus becoming the immunodominant epitopes. CONCLUSIONS-Shifts both in frequency and in immunodominance of CD8ϩ T-cell responses occur more rapidly than do changes in aAb titers. These different kinetics may suggest complementary clinical applications for T-cell and aAb measurements. Diabetes 57:1312-1320, 2008

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The potential of multimer technologies in type 1 diabetes prediction strategies

Fierabracci

2011

Diabetes Metabolism Res

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Type 1 diabetes is an autoimmune disease which occurs in (human leukocyte antigen) genetically predisposed individuals as a consequence of the organ-specific immune destruction of the insulin-producing β cells in the islets of Langherans within the pancreas. Type 1 diabetes is the result of a breakdown in immune regulation that leads to expansion of autoreactive CD4+ and CD8+ T cells, autoantibody-producing B lymphocytes and activation of the innate immune system. Islet-related autoantibodies revealed themselves to be good predictors of future onset of the disease, although they are not directly pathogenetic; T cells instead play a dominant role in disease initiation and progression. In this review, we first discuss the approaches that several laboratories attempted to measure human islet autoantigen-specific T-cell function in type 1 diabetes. T-cell assays could be used in combination with standardized autoantibody screenings to improve predictive strategies. They could also help to monitor in long-term follow-up the efficacy of tolerogenic immunotherapeutic strategies when established at the onset of the disease, and help to predict the recurrence of disease. Although some recent developments based on enzyme-linked immunosorbent spot and immunoblotting techniques have been able to distinguish with good sensitivity and specificity patients from controls, T-cell results, as revealed by international workshops, were indeed largely inconclusive. Nowadays, novel technologies have been exploited that could contribute to answering the tantalizing question of identifying autoreactive T cells. We particularly focus on and discuss MHC multimer tools and emphasize the advantages they can offer but also their weaknesses when used in combination with other T-cell assays. Copyright © 2011 John Wiley & Sons, Ltd.

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Recognition of HLA Class I–Restricted β-Cell Epitopes in Type 1 Diabetes

Cited by 97 publications

References 32 publications

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment

The potential of multimer technologies in type 1 diabetes prediction strategies

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