A multi-epitope DNA vaccine enables a broad engagement of diabetogenic T cells for tolerance in Type 1 diabetes

Postigo-Fernandez, Jorge; Creusot, Rémi J.

doi:10.1016/j.jaut.2018.11.003

Cited by 20 publications

(31 citation statements)

References 47 publications

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“…Nonetheless, Endotope pDNA, but not Proinsulin pDNA, achieved significant delay in disease incidence with both routes, which was consistent with our previous report using the AI/BS mix administered over 8 weeks (23).…”

Section: Resultssupporting

confidence: 92%

“…treatment, and that delivery of a mix of AI and BScontaining pDNA significantly delayed diabetes onset in NOD mice after an 8-week i.m. treatment, similar to the Proinsulin DNA vaccine (23). To follow up on these studies, we evaluated constructs AI versus BS separately to ascertain their relative contribution to disease protection, using continuous treated via i.d.…”

Section: Resultsmentioning

confidence: 99%

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Preclinical evaluation of a precision medicine approach to DNA vaccination in Type 1 diabetes

Creusot

2021

Preprint

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Antigen-specific immunotherapy involves the delivery of self-antigens as proteins or peptides (or using nucleic acids encoding them) to be presented with the goal of inducing tolerance. Approaches employing specific epitopes restricted to the subject's MHC haplotypes have multiplied and offer a more focused and tailored way of targeting autoreactive T cells. In addition, the Endotope platform allows endogenously expressed epitopes to be processed and presented on appropriate MHC class I and II molecules. Here, we evaluated the efficacy of a DNA vaccine encoding epitopes selected and tailored for the non-obese diabetic (NOD) mouse compared to the expression of the proinsulin protein, one of the most successful antigens in prevention of NOD disease, and we assessed the influence of several parameters (e.g. route, dosing frequency) on preventing diabetes onset at normoglycemic and dysglycemic stages. First, encoded peptides should be secreted for effective disease prevention. Furthermore, short weekly treatments with Endotope and proinsulin DNA vaccines delay disease onset, but sustained treatments are required for long-term protection, which was more significant with intradermal delivery. Although epitopes can be presented for at least two weeks, reducing the frequency of antigen administration from weekly to every other week reduced efficacy. Finally, both Endotope and proinsulin DNA vaccines were effective in the dysglycemic stage of disease, but proinsulin provided better protection, particularly in subjects with slower progression of disease. Thus, our data support the possibility of applying a precision medicine approach based on tailored epitopes for the treatment of tissue-specific autoimmune diseases with DNA vaccines.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Preclinical evaluation of a precision medicine approach to DNA vaccination in Type 1 diabetes

Creusot

2021

Preprint

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“…Antigen-specific therapies are tolerogenic approaches that rely on the administration of islet antigens as peptides, whole proteins or DNA vaccines ( 36 , 43 , 104 ). Antigen-specific therapies in general have not been successful so far in inducing durable protection from T1D in autoantibodies positive individuals (stage 1/2 T1D), and current studies focus on potentiating the tolerogenic outcome with combination or more than one epitopes or combination of epitopes with other tolerogenic molecules ( 105 ). DNA-based antigen-specific therapies present several unique advantages, as DNA vectors (plasmids) are easy and cheap to be produced and can guarantee prolonged expression of the encoded antigens and co-expressing factors.…”

Section: How Could the Pd-1/pd-1l Pathway Be Therapeutically Exploitementioning

confidence: 99%

Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes

Falcone

Fousteri

2020

Front. Endocrinol.

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The human pancreas, like almost all organs in the human body, is immunologically tolerated despite the presence of innate and adaptive immune cells that promptly mediate protective immune responses against pathogens in situ. The PD-1/PD-L1 inhibitory pathway seems to play a key role in the maintenance of immune tolerance systemically and within the pancreatic tissue. Tissue resident memory T cells (TRM), T regulatory cells (Treg), macrophages and even β cells exhibit PD-1 or PD-L1 expression that contributes in controlling pancreatic immune homeostasis and tolerance. Dysregulation of the PD-1/PD-L1 axis as shown by animal studies and our recent experience with checkpoint inhibitory blockade in humans can lead to immune dysfunctions leading to chronic inflammatory disease and to type 1 diabetes (T1D) in genetically susceptible individuals. In this review, we discuss the role of the PD-1/PD-L1 axis in pancreatic tissue homeostasis and tolerance, speculate how genetic and environmental factors can regulate the PD-1/PD-L1 pathway, and discuss PD-1/PD-L1-based therapeutic approaches for pancreatic islet transplantation and T1D treatment.

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“…Diabetes mellitus (DM) is a chronic disease that occurs because of the pancreas’ inability to produce enough insulin or when the body cannot effectively use the insulin it produces . DM is a metabolic disorder that affects the metabolism of carbohydrates, fats and protein.…”

Section: Introductionmentioning

confidence: 99%

Novel Pyrazolo[3,4‐d]pyrimidine‐Containing Amide Derivatives: Synthesis, Molecular Docking, In Vitro and In Vivo Antidiabetic Activity

et al. 2019

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A new series of Pyrazolo [3,4-d]pyrimidine containing amide derivatives (8 a-l) were designed, synthesized, and evaluated for their in vitro α-amylase inhibitory activity. The IC 50 values of the target compounds ranged from 1.60 � 0.48 to 2.04 � 1.20 μM as compared to the standard acarbose 1.73 � 0.05 μM. All the Pyrazolo[3,4-d]pyrimidine amide derivatives displayed good inhibitory activities, while seven analogs (8 d, 8 f, 8 g, 8 h, 8 i, 8 j and 8 k) exhibited more or less equipotent activity with IC 50 values 1.77 � 2.84, 1.65 � 0.45, 1.66 � 2.24, 1.73 � 0.37, 1.60 � 0.48, 1.75 � 0.36 and 1.64 � 0.03 μM respectively. Further, the most potent α-amylase inhibitors 8 d and 8 k were also screened for their in vivo antidiabetic activity against alloxan induced diabetic rat model at the dose of 25 and 50 mg/kg. Oral administration of these tested compounds significantly reduced the fasting blood glucose levels in dose dependent manner. The hypoglycemic effects of these compounds were more evident at 3 h and 5 h after administration of tested compounds which was similar to the effect displayed by the positive control. In addition, the binding energies calculated from the docking studies with the α-amylase enzyme (PDB ID: 1HNY) and biological activities indicate that the compounds containing nitro moiety on the phenyl group contributed significantly towards the antidiabetic activity.[a] Dr.

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A multi-epitope DNA vaccine enables a broad engagement of diabetogenic T cells for tolerance in Type 1 diabetes

Cited by 20 publications

References 47 publications

Preclinical evaluation of a precision medicine approach to DNA vaccination in Type 1 diabetes

Preclinical evaluation of a precision medicine approach to DNA vaccination in Type 1 diabetes

Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes

Novel Pyrazolo[3,4‐d]pyrimidine‐Containing Amide Derivatives: Synthesis, Molecular Docking, In Vitro and In Vivo Antidiabetic Activity

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