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.

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.

Using qualitative methods to guide clinical trial design: Parent recommendations for intervention modification in Type 1 diabetes.

2011 ◽  
Vol 25 (6) ◽  
pp. 868-872 ◽  
Author(s):  
Maureen Monaghan ◽  
Risa E. Sanders ◽  
Katherine Patterson Kelly ◽  
Fran R. Cogen ◽  
Randi Streisand
Keyword(s):  
Clinical Trial ◽  
Type 1 Diabetes ◽  
Qualitative Methods ◽  
Trial Design ◽  
Clinical Trial Design

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.

209-OR: ADA Presidents' Select Abstract: Type 1 Diabetes and the Developing Brain—A Longitudinal Study of Brain Growth by the Diabetes Research in Children Network (DirecNet)

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 209-OR ◽  
Author(s):  
ANA MARIA ARBELAEZ ◽  
STEFANI O’DONOGHUE ◽  
NELLY MAURAS ◽  
BRUCE A. BUCKINGHAM ◽  
NEIL H. WHITE ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Longitudinal Study ◽  
Developing Brain ◽  
Diabetes Research ◽  
Brain Growth ◽  
Select Abstract

scholarly journals Prevalence of dental caries in children and adolescents with type 1 diabetes: a systematic review and meta-analysis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yan Wang ◽  
Lin Xing ◽  
Hui Yu ◽  
LiJuan Zhao
Keyword(s):  
Type 1 Diabetes ◽  
Dental Caries ◽  
Children And Adolescents ◽  
Metabolic Control ◽  
Meta Analysis ◽  
Preventive Treatment ◽  
Diabetic Patients ◽  
China National Knowledge Infrastructure ◽  
Pooled Prevalence

Abstract Background Dental caries and type 1 diabetes are responsible for a large burden of global disease; however, the exact prevalence of dental caries among children and adolescents with type 1 diabetes remains controversial, and no quantitative meta-analysis exists. Thus, we performed a meta-analysis to evaluate the prevalence of dental caries among children and adolescents with type 1 diabetes. Methods We performed a systematic search strategy using PubMed, EMBASE and China National Knowledge Infrastructure for relevant studies investigating the prevalence of dental caries in children and adolescents with type 1 diabetes from July 1971 until December 2018. The pooled prevalence with 95% confidence intervals (95%CIs) and subgroup analyses were calculated using a random effects model. Results After screening 358 non-duplicated articles, a total of 10 articles involving 538 individuals were included. The overall prevalence of dental caries among children and adolescents with type 1 diabetes was 67% (95% CI: 0.56–0.77%; I2 = 83%). The prevalence was highest in South America (84%) and lowest in diabetic patients with good metabolic control (47%). Conclusions The prevalence of dental caries was high among children and adolescents with type 1 diabetes. Screening and preventive treatment should be included in dental clinical routines for diabetic children and adolescents, especially in those with poor metabolic control.

scholarly journals CTLA-4 (+49A/G) Polymorphism in Type 1 Diabetes Children of Sudanese Population

2021 ◽  
Vol 08 (01) ◽  
pp. 011-018
Author(s):  
Khalid E. Khalid Kheiralla
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Ethylenediaminetetraacetic Acid ◽  
Negative Regulator ◽  
Cytotoxic Lymphocyte ◽  
Pediatric Clinic ◽  
Homozygous Genotype ◽  
Organ Specific ◽  
Α Helix

Abstract Background Type 1 diabetes mellitus (T1DM) is an organ-specific T cell-mediated autoimmune disease, characterized by destruction of pancreatic islets. Cytotoxic lymphocyte antigen-4 (CTLA-4) is a negative regulator of T cell proliferation, thus conferring susceptibility to autoimmunity. Aims This study aimed to investigate the association of CTLA-4 +49A/G (rs231775) polymorphism with a risk of T1DM in Sudanese children. Methods This a case–control study included 100 children with T1DM, referred to the pediatric clinic at referral pediatric teaching hospital in Gezira State-Sudan. Hundred unrelated healthy controls were recruited from departments in the same hospital. Genomic deoxyribonucleic acid (DNA) was extracted from Ethylenediaminetetraacetic Acid (EDTA)-preserved blood using QIAamp DNA Blood Mini Kit (QIAamp Blood) (QIAGEN; Valencia, CA). The polymerase chain reaction PCR restriction fragment length polymorphism (PCR-RFLP) and sequencing were applied for the CTLA-4 (+49A/G) genotyping. The changes accompanied the polymorphism were evaluated using relevant bioinformatics tools. Results The genotype and allele frequencies of the CTLA-4 (+49A/G) polymorphism were significantly different between the patients and controls (p = 0.00013 and 0.0002, respectively). In particular, the frequency of the G allele, GG homozygous genotype, and AG heterozygous genotype were significantly increased in patients than in controls ([28% versus 7%, odds ratio (OR) = 5.16, 95% confidence interval [CI] = 2.77–9.65, p = 0.00] [12% versus 2%, OR = 6.68, CI = 1.46–30.69, p = 0.01] [32% versus 10%, OR = 4.24, CI = 1.95–9.21, p = 0.00], respectively). The presence of the G allele (homozygous) showed an influence on the signal peptide polarity, hydrophobicity, and α-helix propensity of the CTLA-protein. Conclusion The results further support the association of CTLA-4 (+49A/G) polymorphism and the risk of T1DM in our study population.

scholarly journals Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Vol 9 (6) ◽  
pp. 1177
Author(s):  
Abdulaziz Alhazmi ◽  
Magloire Pandoua Nekoua ◽  
Hélène Michaux ◽  
Famara Sane ◽  
Aymen Halouani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

scholarly journals Peripheral autoreactive CD8 T‐cell frequencies are too variable to be a reliable predictor of disease progression of human type 1 diabetes

2021 ◽  
Vol 10 (7) ◽  
Author(s):  
Johnna D Wesley ◽  
Susanne Pfeiffer ◽  
Darius Schneider ◽  
David Friedrich ◽  
Nikole Perdue ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Disease Progression ◽  
Cd8 T Cell ◽  
Human Type ◽  
Reliable Predictor ◽  
Human Type 1 Diabetes
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