Microencapsulated G3C Hybridoma Cell Graft Delays the Onset of Spontaneous Diabetes in NOD Mice by an Expansion of Gitr+ Treg Cells.
Luigi CariPia MontanucciGiuseppe BastaMaria G PetrilloErika RicciTeresa PescaraAlessia GrecoSabrina CiprianiJun ShimizuGraziella MiglioratiGiuseppe NocentiniRiccardo CalafioreCarlo RiccardiPublished in: Diabetes (2020)
As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3+ Treg-cell expansion in the spleen of wild-type mice but not in Gitr-/- mice. G3C/cps also induced the expansion of nonconventional Cd4+Cd25-/lowFoxp3lowGitrint/high (GITR single-positive [sp]) Tregs. Both Cd4+Cd25+GitrhighFoxp3+ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.
Keyphrases
- wild type
- induced apoptosis
- type diabetes
- high fat diet induced
- regulatory t cells
- monoclonal antibody
- cardiovascular disease
- cell cycle arrest
- diabetic rats
- oxidative stress
- glycemic control
- insulin resistance
- stem cells
- cell death
- dendritic cells
- signaling pathway
- metabolic syndrome
- risk assessment
- multiple sclerosis
- clinical trial
- climate change
- cell therapy
- single cell
- bone marrow
- pi k akt
- binding protein
- innate immune
- placebo controlled