scholarly journals T Cell Epitopes and Neo-epitopes in Type 1 Diabetes: A Comprehensive Update and Reappraisal

2020 ◽  
Author(s):  
Ada Admin ◽  
Eddie A. James ◽  
Roberto Mallone ◽  
Sally C. Kent ◽  
Teresa P. DiLorenzo
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Hla Class I ◽  
Diabetes Research ◽  
T Cell Epitopes ◽  
Online Appendix ◽  
Cell Monitoring

The autoimmune disease type 1 diabetes is characterized by effector T cell responses to pancreatic beta cell-derived peptides presented by HLA class I and class II molecules, leading ultimately to beta cell demise and insulin insufficiency. Although a given HLA molecule presents a vast array of peptides, only those recognized by T cells are designated as epitopes. Given their intimate link to etiology, the discovery and characterization of T cell epitopes is a critical aspect of type 1 diabetes research. Understanding epitope recognition is also crucial for the pursuit of antigen-specific immunotherapies and implementation of strategies for T cell monitoring. For these reasons, a cataloging and appraisal of the T cell epitopes targeted in type 1 diabetes was completed over a decade ago, providing an important resource for both the research and the clinical communities. Here we present a much-needed update and reappraisal of this earlier work, and include an online appendix that cross-indexes each epitope with its primary references and Immune Epitope Database (IEDB) identifier. Our analysis includes a grading scale to score the degree of evidence available for each epitope, which conveys our perspective on several useful criteria for epitope evaluation. While providing an efficient summary of the arguably impressive current state of knowledge, this work also brings to light several deficiencies. These include the need for improved epitope validation, as few epitopes score highly by the criteria employed, and the dearth of investigations of the epitopes recognized in the context of several under-studied type 1 diabetes-associated HLA molecules.

scholarly journals T Cell Epitopes and Neo-epitopes in Type 1 Diabetes: A Comprehensive Update and Reappraisal

2020 ◽  
Author(s):  
Ada Admin ◽  
Eddie A. James ◽  
Roberto Mallone ◽  
Sally C. Kent ◽  
Teresa P. DiLorenzo
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Hla Class I ◽  
Diabetes Research ◽  
T Cell Epitopes ◽  
Online Appendix ◽  
Cell Monitoring

The autoimmune disease type 1 diabetes is characterized by effector T cell responses to pancreatic beta cell-derived peptides presented by HLA class I and class II molecules, leading ultimately to beta cell demise and insulin insufficiency. Although a given HLA molecule presents a vast array of peptides, only those recognized by T cells are designated as epitopes. Given their intimate link to etiology, the discovery and characterization of T cell epitopes is a critical aspect of type 1 diabetes research. Understanding epitope recognition is also crucial for the pursuit of antigen-specific immunotherapies and implementation of strategies for T cell monitoring. For these reasons, a cataloging and appraisal of the T cell epitopes targeted in type 1 diabetes was completed over a decade ago, providing an important resource for both the research and the clinical communities. Here we present a much-needed update and reappraisal of this earlier work, and include an online appendix that cross-indexes each epitope with its primary references and Immune Epitope Database (IEDB) identifier. Our analysis includes a grading scale to score the degree of evidence available for each epitope, which conveys our perspective on several useful criteria for epitope evaluation. While providing an efficient summary of the arguably impressive current state of knowledge, this work also brings to light several deficiencies. These include the need for improved epitope validation, as few epitopes score highly by the criteria employed, and the dearth of investigations of the epitopes recognized in the context of several under-studied type 1 diabetes-associated HLA molecules.

High-throughput Screening for CD8+ T Cell Epitopes Targeted in Type 1 Diabetes

2010 ◽  
Vol 135 ◽  
pp. S19
Author(s):  
Brian Hondowicz ◽  
Katharine Schwedhelm ◽  
Arnold Kas ◽  
Michael Tasch ◽  
Nirasha Ramchurren ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cd8 T Cell ◽  
T Cell Epitopes

scholarly journals The acquisition of an insulin-secreting phenotype by HGF-treated rat pancreatic ductal cells (ARIP) is associated with the development of susceptibility to cytokine-induced apoptosis

2005 ◽  
Vol 34 (2) ◽  
pp. 367-376 ◽  
Author(s):  
E Anastasi ◽  
C Santangelo ◽  
A Bulotta ◽  
F Dotta ◽  
B Argenti ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cells ◽  
Interleukin 1 ◽  
Pancreatic Beta Cell ◽  
Necrosis Factor Alpha ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Induced Apoptosis

The elucidation of mechanisms regulating the regeneration and survival of pancreatic beta cells has fundamental implications in the cell therapy of type 1 diabetes. The present study had the following three aims: 1. to investigate whether pancreatic ductal epithelial cells can be induced to differentiate into insulin-producing cells by exposing them to hepatocyte growth factor (HGF); 2. to characterize some of the molecular events leading to their differentiation toward a beta-cell-like phenotype; 3. to evaluate the susceptibility of newly differentiated insulin-secreting cells to cytokine-induced apoptosis, a mechanism of beta-cell destruction occurring in type 1 diabetes. We demonstrated that HGF-treated rat pancreatic ductal cell line (ARIP) cells acquired the capability to transcribe the insulin gene and translate its counterpart protein. HGF-treated cells also exhibited a glucose-dependent capability to secrete insulin into the cultured medium. Expression analysis of some of the genes regulating pancreatic beta-cell differentiation revealed a time-dependent transcription of neurogenin-3 and Neuro-D in response to HGF. Finally, we determined the susceptibility to proinflammatory cytokine (PTh1)-induced apoptosis by incubating HGF-treated and untreated ARIP cells with a cocktail of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Such treatment induced apoptotic death, as determined by the TUNEL technique, in about 40% of HGF-treated, insulin-secreting ARIP cells, while untreated ARIP cells were resistant to PTh1-induced apoptosis. In conclusion, we showed that HGF promotes the differentiation of ARIP cells into pancreatic beta-cell-like cells, and that the differentiation toward an insulin-secreting phenotype is associated with the appearance of susceptibility to cytokine-induced apoptosis.

Perforin facilitates beta cell killing and regulates autoreactive CD8 + T‐cell responses to antigen in mouse models of type 1 diabetes

2015 ◽  
Vol 94 (4) ◽  
pp. 334-341 ◽  
Author(s):  
Prerak Trivedi ◽  
Kate L Graham ◽  
Balasubramaninan Krishnamurthy ◽  
Stacey Fynch ◽  
Robyn M Slattery ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cell ◽  
Mouse Models ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Killing ◽  
Cell Responses

scholarly journals APPL1 prevents pancreatic beta cell death and inflammation by dampening NFκB activation in a mouse model of type 1 diabetes

Diabetologia ◽  
2016 ◽  
Vol 60 (3) ◽  
pp. 464-474 ◽  
Author(s):  
Xue Jiang ◽  
Yawen Zhou ◽  
Kelvin K. L. Wu ◽  
Zhanrui Chen ◽  
Aimin Xu ◽  
...  
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Mouse Model ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Beta Cell Death

scholarly journals Establishment of T cell lines to bovine beta-casein and beta-casein-derived epitopes in patients with type 1 diabetes

2003 ◽  
Vol 176 (1) ◽  
pp. 143-150 ◽  
Author(s):  
L Monetini ◽  
F Barone ◽  
L Stefanini ◽  
A Petrone ◽  
T Walk ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Diabetic Patients ◽  
Beta Casein ◽  
T Cell Lines ◽  
Human Insulinoma

Enhanced cellular immune response to bovine beta-casein has been reported in patients with type 1 diabetes. In this study we aimed to establish beta-casein-specific T cell lines from newly diagnosed type 1 diabetic patients and to characterise these cell lines in terms of phenotype and epitope specificity. Furthermore, since sequence homologies exist between beta-casein and putative beta-cell autoantigens, reactivity to the latter was also investigated. T cell lines were generated from the peripheral blood of nine recent onset type 1 diabetic patients with different HLA-DQ and -DR genotypes, after stimulation with antigen pulsed autologous irradiated antigen presenting cells (APCs) and recombinant human interleukin-2 (rhIL-2). T cell line reactivity was evaluated in response to bovine beta-casein, to 18 overlapping peptides encompassing the whole sequence of beta-casein and to beta-cell antigens, including the human insulinoma cell line, CM, and a peptide from the beta-cell glucose transporter, GLUT-2. T cell lines specific to beta-casein could not be isolated from HLA-matched and -unmatched control subjects. beta-Casein T cell lines reacted to different sequences of the protein, however a higher frequency of T cell reactivity was observed towards the C-terminal portion (peptides B05-14, and B05-17 in 5/9 and 4/9 T cell lines respectively). Furthermore, we found that 1 out of 9 beta-casein-specific T cell lines reacted also to the homologous peptide from GLUT-2, and that 3 out of 4 of tested cell lines reacted also to extracts of the human insulinoma cell line, CM. We conclude that T cell lines specific to bovine beta-casein can be isolated from the peripheral blood of patients with type 1 diabetes; these cell lines react with multiple and different sequences of the protein particularly towards the C-terminal portion. In addition, reactivity of beta-casein T cell lines to human insulinoma extracts and GLUT-2 peptide was detected, suggesting that the potential cross-reactivity with beta-cell antigens deserves further investigation.

Androgen receptor: a new player associated with apoptosis and proliferation of pancreatic beta-cell in type 1 diabetes mellitus

APOPTOSIS ◽  
2008 ◽  
Vol 13 (8) ◽  
pp. 959-971 ◽  
Author(s):  
Ru-Jiang Li ◽  
Shu-Dong Qiu ◽  
Hai-Xu Wang ◽  
Hong Tian ◽  
Li-Rong Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Androgen Receptor ◽  
Beta Cell ◽  
Type 1 Diabetes Mellitus ◽  
Pancreatic Beta Cell

scholarly journals Challenges to Reshape the Future of Type 1 Diabetes Research

2018 ◽  
Vol 103 (8) ◽  
pp. 2838-2842 ◽  
Author(s):  
David Bleich ◽  
David H Wagner
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Trial Design ◽  
Evidence Synthesis ◽  
Clinical Trial Design ◽  
Preventive Treatment ◽  
Diabetes Research ◽  
Knowledge Gaps ◽  
Disease Stratification

Abstract Context Immunotherapy trials to prevent type 1 diabetes have been unsuccessful for >15 years. Understanding pitfalls and knowledge gaps in the immunology of type 1 diabetes should lead us in new directions that will yield better trial outcomes. A proposal is made for precision medicine trial design in future type 1 diabetes studies. Evidence Acquisition High-quality peer-reviewed basic science and clinical research trials for type 1 diabetes were used in this Perspective article. Type 1 diabetes publications were reviewed from 2000 to 2018 by using Google Scholar and PubMed reference databases. Evidence Synthesis Personalized medicine for type 1 diabetes should recognize that each individual has phenotypic and genotypic quirks that distinguish them from other study participants. A uniform protocol for antigen-specific immunotherapy has consistently failed to prevent disease. An alternative approach using molecular tools to personalize the preventive treatment strategy might be a road forward for type 1 diabetes research. Assumptions or lack of knowledge about disease stratification (not all type 1 diabetes is the same disease), individualized antigen-specific T cells, regulatory T-cell populations, and T-cell receptor rearrangement are just a few aspects of immunology that require integration with clinical trial design. Conclusions The type 1 diabetes research community continues to bring forward novel immunotherapy trials to prevent disease, but this approach is unlikely to succeed until several fundamental aspects of clinical immunology are recognized and addressed. Here, we identify several knowledge gaps that could rectify type 1 diabetes trial design and lead to future success.

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