Proinsulin-mediated induction of type 1 diabetes in HLA-DR4-transgenic mice

Verhagen, Johan; Smith, Emma; Whettlock, Emily M.; Macintyre, Benedict; Peakman, Mark

doi:10.1038/s41598-018-32546-4

Cited by 14 publications

(15 citation statements)

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“…HLA-DR3-DQ2-transgenic mice (C57BL/6- H2 dlAb1-Ea Tg(Cd4-CD4)2362Litt Tg(HLA DR3-DQ2)303, described previously [10], and obtained from J. McCluskey [University of Melbourne, VIC, Australia]) were crossed with RIP-B7.1-transgenic mice (B6.Cg-Tg( Ins2 -CD80)3B7Flv/Orl; ID 00216; EMMA, Orleans, France) in order to obtain HLA-DR3-DQ2 + huCD4 + IA/IE −/− RIP.B7.1 + mice, hereafter referred to as DR3DQ2×RIP-B7.1. DR4×RIP-B7.1 mice, generated by crossing B6.129S2- H2-Ab1 tm1Gru Tg(HLA-DRA/H2-Ea,HLA-DRB1 * 0401/H2-Eb)1Kito mice (Taconic, Germantown, MD, USA) with B6.Cg-Tg( Ins2 -CD80)3B7Flv/Orl mice, were described previously [11]. All mice were kept under specific-pathogen-free conditions, in individually ventilated cages, at the King’s College London Biological Services Unit on 12 h light–dark cycles with food and water provided ad libitum.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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Aims/hypothesisThe 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.MethodsWe 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.ResultsHLA-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/interpretationOur 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.Electronic supplementary materialThe online version of this article (10.1007/s00125-019-04994-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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“…(i) immune-deficient mice that are transplanted with human cells [24, 25] and (ii) NOD mice that have been genetically manipulated to express relevant human genes [26, 27]. Human cell transplant models vary depending upon the donor cells and must be reestablished for each experiment.…”

Section: Introductionmentioning

confidence: 99%

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

Elso

Scott

Mariana

et al. 2019

Preprint

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2 16 Abstract 17 Type 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-18 producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop 19 autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been 20 the preeminent murine model for human type 1 diabetes research for several decades. However, 21 humanized mouse models are highly sought after because they offer both the experimental 22 tractability of a mouse model and the clinical relevance of human-based research. Autoimmune 23 T-cell responses against insulin, and its precursor proinsulin, play central roles in the 24 autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first 25 step towards developing a murine model of the human autoimmune response against pancreatic 26 beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene 27 (INS) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin 28 in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-29 peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild 30 type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15-20% of HuPI 31 mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice.32 Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days 33 but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 34 to create mouse models of human diseases that express proteins pivotal to the human disease.35 Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes. 36 3 37 Introduction 38 Type 1 diabetes (T1D) is an autoimmune disease caused by the T-cell mediated destruction of 39 the pancreatic, insulin-producing beta cells [1, 2]. This leads to a primary insulin deficiency and 40 subsequent metabolic disease [3]. Since its discovery in 1980 [4], the Non-obese diabetic (NOD) 41 mouse has been the preferred mouse model for research into human T1D. Autoimmune diabetes 42 in the NOD mouse shares many pathological features with human type 1 diabetes [5]. For 43 example, diabetes develops spontaneously, the MHC II genes greatly impact upon susceptibility 44 and immune-cell infiltration of the islets of Langerhans is observed [6]. 45 46 Many autoantigens have been implicated in the immune pathogenesis of human T1D and NOD 47 autoimmune diabetes [7, 8]. However, T cells specific for insulin, and its precursor proinsulin, 48 have been shown to cause diabetes in the NOD mouse [9-11]. Although pathogenesis cannot be 49 measured directly in humans, T-cell responses to (pro)insulin are strongly implicated in human 50 type 1 diabetes [12-15]. Humans carry one insulin gene (INS), whereas the mouse genome 51 contains two nonallelic insulin genes, Ins1 (chromosome 19) and Ins2 (chromosome 7) [16]. Ins152 is predomin...

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“…For these reasons, HLA transgenic mice were among the first “humanized” animal models of autoimmune diseases [ [2] , [3] , [4] , [5] ]. These models have become even more sophisticated by introducing additional genetic mutations, such as a recent study that created C57BL/6 mice lacking mouse MHC II and instead expressing human HLA-DR4, a high risk allele for T1D development, and human CD80, for additional co-stimulation of T cells [ 6 ]. Upon immunization with murine proinsulin-2, these mice developed a disease similar to human T1D [ 6 ], with myeloid and lymphoid murine cell infiltration into the pancreatic islets and the production of insulin-reactive autoantibodies [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

The development of human immune system mice and their use to study tolerance and autoimmunity

Costa

Lang

Torres

et al. 2019

Journal of Translational Autoimmunity

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Autoimmune diseases evolve from complex interactions between the immune system and self-antigens and involve several genetic attributes, environmental triggers and diverse cell types. Research using experimental mouse models has contributed key knowledge on the mechanisms that underlie these diseases in humans, but differences between the mouse and human immune systems can and, at times, do undermine the translational significance of these findings. The use of human immune system (HIS) mice enables the utility of mouse models with greater relevance for human diseases. As the name conveys, these mice are reconstituted with mature human immune cells transferred directly from peripheral blood or via transplantation of human hematopoietic stem cells that nucleate the generation of a complex human immune system. The function of the human immune system in HIS mice has improved over the years with the stepwise development of better models. HIS mice exhibit key benefits of the murine animal model, such as small size, robust and rapid reproduction and ease of experimental manipulation. Importantly, HIS mice also provide an applicable in vivo setting that permit the investigation of the physiological and pathological functions of the human immune system and its response to novel treatments. With the gaining popularity of HIS mice in the last decade, the potential of this model has been exploited for research in basic science, infectious diseases, cancer, and autoimmunity. In this review we focus on the use of HIS mice in autoimmune studies to stimulate further development of these valuable models.

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Proinsulin-mediated induction of type 1 diabetes in HLA-DR4-transgenic mice

Cited by 14 publications

References 13 publications

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

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

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

The development of human immune system mice and their use to study tolerance and autoimmunity

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