Antigen-Based Immune Therapeutics for Type 1 Diabetes: Magic Bullets or Ordinary Blanks?

The ideal drug of modern medicine is the one that achieves its therapeutic target with minimal adverse effects. Immune therapy of Type 1 diabetes (T1D) is no exception, and knowledge of the antigens targeted by pathogenic T cells offers a unique opportunity towards this goal. Different antigen formulations are being considered, such as proteins or peptides, either in their native form or modified ad hoc, DNA plasmids, and cell-based agents. Translation from mouse to human should take into account important differences, particularly in the time scale of autoimmune progression, and intervention. Critical parameters such as administration route, dosing and interval remain largely empirical and need to be further dissected. T1D staging through immune surrogate markers before and after treatment will be key in understanding therapeutic actions and to finally turn ordinary blanks into magic bullets

Environmental Triggering of Type 1 Diabetes Autoimmunity

Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic islet β cells are destroyed by immune cells, ultimately leading to overt diabetes. The progressive increase in T1D incidence over the years points to the role of environmental factors in triggering or accelerating the disease process which develops on a highly multigenic susceptibility background. Evidence that environmental factors induce T1D has mostly been obtained in animal models. In the human, associations between viruses, dietary habits or changes in the microbiota and the development of islet cell autoantibodies or overt diabetes have been reported. So far, prediction of T1D development is mostly based on autoantibody detection. Future work should focus on identifying a causality between the different environmental risk factors and T1D development to improve prediction scores. This should allow developing preventive strategies to limit the T1D burden in the future

Déviation de l'auto-immunité chez la souris NOD invalidée pour la voie ICOS/ICOSL

Le modèle murin le plus utilisé pour le diabète de type 1 est la souris NOD. L activation des lymphocytes T autoréactifs vis à vis des cellules béta nécessite la reconnaissance par le TCR de l auto antigène présenté par le CMH ainsi que des signaux de co stimulation. Nous apportons la preuve que la voie de costimulation ICOS/ICOSL est indispensable au développement du diabète chez la souris NOD. En effet, les souris invalidées pour le gène Icos ou IcosL sont protégées du diabète. Nous avons démontré que cette protection est liée à un défaut d activation des LT diabétogènes. De façon inattendue, nous avons observé chez ces souris ICOS-/- et ICOSL-/- une neuromyopathie. Cette pathologie se développe parallèlement au diabète chez la souris ICOSL+/+. Sur le plan histologique, le muscle strié périphérique et le nerf périphérique est envahi par un infiltrat lymphocytaire et par des cellules présentatrices d antigène. Nous avons démontré par des expériences de transfert adoptif que la neuromyopathie est une maladie auto-immune données, nous avons étudié les souris NOD ICOSL-/- CIITA-/-. Ces souris sont dépourvues de lymphocytes T -CD4+ et ne développent pas de neuromyopathie ni de diabète. De même, nous avons étudié les souris NOD ICOSL-/- béta2m-/-. Ces souris sont dépourvues de lymphocytes T-CD8+ et développent une neuromyopathie. Cette déviation de l auto-immunité est liée à l interaction entre les LT et les lymphocytes B via le signal ICOS/ICOSL. Nous avons prouvé via des expériences de transfert et de chimères que l absence de signal ICOS/ICOSL entre les lymphocytes T et les lymphocytes B oriente l auto-immunité vers le système nerveux périphérique et le muscle strié. Enfin, l analyse du spectre de spécificité des anticorps présent chez la souris ICOSL-/- par western blot puis par spectrométrie de masse a précisé les cibles antigéniques de la myopathie. L invalidation de la voie ICOS/ICOSL conduit donc à une déviation de l auto-immunité du pancréas vers le muscle et le système nerveux périphérique. Ces données prouvent que la voie ICOS/ICOSL est indispensable à l initiation du diabète, mais aussi au contrôle de l auto-immunitéCostimulation pathways are described as central in T cell activation and the control of autoimmune responses. We previously reported that NOD mice that are deficient for the icosl gene are protected from diabetes, but instead develop a spontaneous autoimmune neuromyopathy. The general phenotype of the neuromyopathy observed in ICOSL-/- NOD mice is globally similar to that observed in ICOS-/- and ICOS-/-ICOSL-/- double knockout NOD mice. The neuromyopathy is observed in 100% of female mice by the age of 35 weeks. The neuropathy remains limited to the peripheral nerve tissue. The disease is characterized by an infiltration of immune cells: CD4+ T cells, CD8+ T cells, dendritic cells and B lymphocytes, but does not extend to the central nervous system. A similar infiltrate is seen in muscles. Autoimmune neuromyopathy can be transfer to naive recipients by T lymphocytes. Transfer is achieved in NOD.scid recipient mice by CD4+ T-cells, although not by CD8+ T-cells, isolated from 35 week old ICOSL-/- NOD. The predominant role of CD4+T-cells is further demonstrated in this model by the observation that CIITA-/-ICOSL-/- NOD mice do not developed the neuromyopathy. By contrast, u2m-/-ICOSL-/- NOD mice develop a neuromyopathy. We obtained evidence (in chimeric mice) that the interaction between antigen-presenting cells (APC) and T lymphocytes via ICOS/ICOSL is a prerequisite to the development of diabetes, while the loss of the interaction between T lymphocytes and APC play a key role in the development of nervous and muscular autoimmunity. Finally, the spectrum analysis of antibodies specificity in mouse ICOSL-/- with Western blot and mass spectrometry indicated the antigenic targets of myopathy. Altogether, our data indicate that the deviation of autoimmunity in NOD mice from the pancreas to muscles and the peripheral nervous system in the absence of ICOS/ICOSL signal is dependent on the loss of the physiological interaction between T cells and APCPARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Insulin Secretion: Movement at All Levels

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Impact of Treatment on Islet Function in Type 2 Diabetes

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First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes

: Background : Type 1 diabetes (T1D) is a CD4+ T cell-driven autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by CD8+ T cells. Achieving glycemic targets in T1D remains challenging in clinical practice; new treatments aim to halt autoimmunity and prolong β-cell survival. IMCY-0098 is a peptide derived from human proinsulin that contains a thiol-disulfide oxidoreductase motif at the N-terminus and was developed to halt disease progression by promoting the specific elimination of pathogenic T cells. Methods: This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were randomized to receive four bi-weekly injections of placebo or increasing doses of IMCY-0098 (dose groups A/B/C received 50/150/450 μg for priming followed by three further administrations of 25/75/225 μg, respectively). Multiple T1D-related clinical parameters were also assessed to monitor disease progression and inform future development. Long-term follow-up to 48 weeks was also conducted in a subset of patients. Results: Treatment with IMCY-0098 was well tolerated with no systemic reactions; a total of 315 adverse events (AEs) were reported in 40 patients (97.6%) and were related to study treatment in 29 patients (68.3%). AEs were generally mild; no AE led to discontinuation of the study or death. No significant decline in C-peptide was noted from baseline to Week 24 for dose A, B, C, or placebo (mean change − 0.108, − 0.041, − 0.040, and − 0.012, respectively), suggesting no disease progression. Conclusions: Promising safety profile and preliminary clinical response data support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. Trial registration: IMCY-T1D-001: ClinicalTrials.gov NCT03272269; EudraCT: 2016–003514-27; and IMCY-T1D-002: ClinicalTrials.gov NCT04190693; EudraCT: 2018–003728-35

Viral infection prevents diabetes by inducing regulatory T cells through NKT cell–plasmacytoid dendritic cell interplay

iNKT cell and pDC cross talk prevents type 1 diabetes by inducing T reg cells in the pancreatic lymph node during viral infection

Meta-analysis of genome-wide association studies for cattle stature identifies common genes that regulate body size in mammals

peer-reviewedH.D.D., A.J.C., P.J.B. and B.J.H. would like to acknowledge the Dairy Futures Cooperative Research Centre for funding. H.P. and R.F. acknowledge funding from the German Federal Ministry of Education and Research (BMBF) within the AgroClustEr ‘Synbreed—Synergistic Plant and Animal Breeding’ (grant 0315527B). H.P., R.F., R.E. and K.-U.G. acknowledge the Arbeitsgemeinschaft Süddeutscher Rinderzüchter, the Arbeitsgemeinschaft Österreichischer Fleckviehzüchter and ZuchtData EDV Dienstleistungen for providing genotype data. A. Bagnato acknowledges the European Union (EU) Collaborative Project LowInputBreeds (grant agreement 222623) for providing Brown Swiss genotypes. Braunvieh Schweiz is acknowledged for providing Brown Swiss phenotypes. H.P. and R.F. acknowledge the German Holstein Association (DHV) and the Confederación de Asociaciones de Frisona Española (CONCAFE) for sharing genotype data. H.P. was financially supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (DFG) (grant PA 2789/1-1). D.B. and D.C.P. acknowledge funding from the Research Stimulus Fund (11/S/112) and Science Foundation Ireland (14/IA/2576). M.S. and F.S.S. acknowledge the Canadian Dairy Network (CDN) for providing the Holstein genotypes. P.S. acknowledges funding from the Genome Canada project entitled ‘Whole Genome Selection through Genome Wide Imputation in Beef Cattle’ and acknowledges WestGrid and Compute/Calcul Canada for providing computing resources. J.F.T. was supported by the National Institute of Food and Agriculture, US Department of Agriculture, under awards 2013-68004-20364 and 2015-67015-23183. A. Bagnato, F.P., M.D. and J.W. acknowledge EU Collaborative Project Quantomics (grant 516 agreement 222664) for providing Brown Swiss and Finnish Ayrshire sequences and genotypes. A.C.B. and R.F.V. acknowledge funding from the public–private partnership ‘Breed4Food’ (code BO-22.04-011- 001-ASG-LR) and EU FP7 IRSES SEQSEL (grant 317697). A.C.B. and R.F.V. acknowledge CRV (Arnhem, the Netherlands) for providing data on Dutch and New Zealand Holstein and Jersey bulls.Stature is affected by many polymorphisms of small effect in humans1. In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P < 5 × 10−8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP–seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals

Rôle de l'insuline dans la rupture de tolérance chez la souris NOD

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF