scholarly journals Proinsulin peptide promotes autoimmune diabetes in a novel HLA-DR3-DQ2-transgenic murine model of spontaneous disease

Diabetologia ◽  
2019 ◽  
Vol 62 (12) ◽  
pp. 2252-2261 ◽  
Author(s):  
Johan Verhagen ◽  
Norkhairin Yusuf ◽  
Emma L. Smith ◽  
Emily M. Whettlock ◽  
Kerina Naran ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Diabetes Incidence ◽  
Human Type ◽  
Insulin Promoter ◽  
Human Type 1 Diabetes ◽  
Hla Dr3 ◽  
Peptide Region

Abstract Aims/hypothesis The molecular basis for the pathological impact of specific HLA molecules on autoimmune diseases such as type 1 diabetes remains unclear. Recent natural history studies in children have indicated a link between specific HLA genotypes and the first antigenic target against which immune responses develop. We set out to examine this link in vivo by exploring the diabetogenicity of islet antigens on the background of a common diabetes-associated HLA haplotype. Methods We generated a novel HLA-transgenic mouse model that expresses high-risk genes for type 1 diabetes (DRB1*03:01-DQA1*05:01-DQB1*02:01) as well as human CD80 under the rat insulin promoter and human CD4, on a C57BL/6 background. Adjuvanted antigen priming was used to reveal the diabetogenicity of candidate antigens and peptides. Results HLA-DR3-DQ2+huCD4+IA/IE−/−RIP.B7.1+ mice spontaneously developed autoimmune diabetes (incidence 46% by 35 weeks of age), accompanied by numerous hallmarks of human type 1 diabetes (autoantibodies against GAD65 and proinsulin; pancreatic islet infiltration by CD4+, CD8+ B220+, CD11b+ and CD11c+ immune cells). Disease was markedly accelerated and had deeper penetrance after adjuvanted antigen priming with proinsulin (mean onset 11 weeks and incidence 100% by 20 weeks post challenge). Moreover, the diabetogenic effect of proinsulin located to the 15-residue B29-C11 region. Conclusions/interpretation Our study identifies a proinsulin-derived peptide region that is highly diabetogenic on the HLA-DR3-DQ2 background using an in vivo model. This approach and the peptide region identified may have wider implications for future studies of human type 1 diabetes.

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

2011 ◽  
Vol 186 (6) ◽  
pp. 3787-3797 ◽  
Author(s):  
Eva Codina-Busqueta ◽  
Erika Scholz ◽  
Pau M. Muñoz-Torres ◽  
Carme Roura-Mir ◽  
Manuela Costa ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Pancreatic Islets ◽  
Human Type ◽  
Human Type 1 Diabetes

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

scholarly journals Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

2017 ◽  
Vol 17 (10) ◽  
Author(s):  
Sally C. Kent ◽  
Stuart I. Mannering ◽  
Aaron W. Michels ◽  
Jenny Aurielle B. Babon
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Human Type ◽  
Human Type 1 Diabetes

scholarly journals Replacing murine insulin 1 with human insulin protects NOD mice from diabetes

2019 ◽  
Author(s):  
Colleen M. Elso ◽  
Nicholas A. Scott ◽  
Lina Mariana ◽  
Emma I. Masterman ◽  
Andrew P.R. Sutherland ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Mouse Models ◽  
Human Insulin ◽  
Murine Model ◽  
Pancreatic Beta Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Human Type 1 Diabetes

AbstractType 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse model and the clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (INS) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15-20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.

scholarly journals Low-Dose Otelixizumab Anti-CD3 Monoclonal Antibody DEFEND-1 Study: Results of the Randomized Phase III Study in Recent-Onset Human Type 1 Diabetes

Diabetes Care ◽  
2014 ◽  
Vol 37 (10) ◽  
pp. 2746-2754 ◽  
Author(s):  
Ronnie Aronson ◽  
Peter A. Gottlieb ◽  
Jens S. Christiansen ◽  
Thomas W. Donner ◽  
Emanuele Bosi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Type 1 Diabetes ◽  
Low Dose ◽  
Phase Iii ◽  
Recent Onset ◽  
Human Type ◽  
Study Results ◽  
Phase Iii Study ◽  
Human Type 1 Diabetes
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