Abstract
Induction of long-term tolerance to β-cell autoantigens has been investigated both in animal models and in human type 1 diabetes (T1D) in order to prevent the disease. As regards external compounds, the dietary plant protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was lowered. Intranasal gliadin also rescued a fraction of prediabetic 13-week-old NOD mice from progressing to clinical onset of diabetes compared to OVA-treated controls. Vaccination with i.n. gliadin led to an induction of CD4+Foxp3+ T cells and even more significant induction of γδ T cells in mucosal, but not in non-mucosal lymphoid compartments. This prevention strategy was characterized by an increased proportion of IL-10 and a decreased proportion of IL-2, IL-4 and IFN-γ-positive CD4+Foxp3+ T cells, and IFN-γ-positive γδ T cells, preferentially in mucosal lymphoid organs. In conclusion, i.n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D.
Highlights
The incidence of type 1 diabetes mellitus (T1D) has been rapidly increasing during the past decades [1]
As shown in Fig. 1., five intranasal administrations of gliadin (50 mg) to 4-week-old NOD females significantly decreased the diabetes incidence to 56% in comparison to mice treated with OVA with a diabetes incidence of 100%, p = 0.001 and to phosphate-buffered saline (PBS)-treated controls (94%, p = 0.008)
We have shown that five intranasal administrations of 50 mg gliadin in 4-week-old NOD mice significantly reduce penetrance of diabetes as well as the level of insulitis
Summary
The incidence of type 1 diabetes mellitus (T1D) has been rapidly increasing during the past decades [1]. In animal models of T1D, mucosal administration of b-cell related autoantigens is a well-established strategy for disease prevention by induction of islet-specific T regulatory cells (Tregs) that may prevent the autoimmune aggression locally by mechanism of bystander suppression [3]. Mucosal administration of insulin [4,5] or GAD [6], GAD65 peptide [7] as well as proinsulin or insulin peptides [8,9] has led to prevention of T1D in animal models. Several of the autoantigens have been used in recent human trials, but at present, there is no established prevention strategy available for human T1D [10,11]
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