Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β cells by autoantigen-reactive diabetogenic cells. Antigen-specific therapies using islet autoantigens for restoring immune tolerance have emerged as promising approaches for the treatment of T1D but have been unsuccessful in humans. Herein, we report that RGI-3100-iB, a novel liposomal formulation carrying both α-galactosylceramide (α-GalCer), which is a representative ligand for invariant natural killer T (iNKT) cells, and insulin B chain 9–23 peptide, which is an epitope for CD4+ T cells, could induce the accumulation of regulatory T cells (Tregs) in islets in a peptide-dependent manner, followed by the remarkable prevention of diabetes onset in nonobese diabetic (NOD) mice. While multiple administrations of a monotherapy using either α-GalCer or insulin B peptide in a liposomal formulation was confirmed to delay/prevent T1D in NOD mice, RGI-3100-iB synergistically enhanced the prevention effect of each monotherapy and alleviated insulitis in NOD mice. Immunopathological analysis showed that Foxp3+ Tregs accumulated in the islets in RGI-3100-iB-treated mice. Cotransfer of diabetogenic T cells and splenocytes of NOD mice treated with RGI-3100-iB, but not liposomal α-GalCer encapsulating an unrelated peptide, to NOD-SCID mice resulted in the prevention of diabetes and elevation of Foxp3 mRNA expression in the islets. These data indicate that the migration of insulin B-peptide-specific Tregs to islet of NOD mice that are involved in the suppression of pathogenic T cells related to diabetes onset and progression could be enhanced by the administration of liposomes containing α-GalCer and insulin B peptide.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive destruction of pancreatic β cells by diabetogenic CD4+ and CD8+ T cells and B cells, which have loss of immunological tolerance and react with defined islet proteins, such as insulin [1]
An antigen-nonspecific therapy and an antigen-specific therapy have been tested in clinical trials [4,5,6,7], but there is no cure Journal of Diabetes Research for T1D, as of date [8]
We have previously reported that a novel liposomal formulation carrying an antigenic polypeptide and α-galactosylceramide (α-GalCer), an activator of invariant natural killer T cells, induced the antigen-specific Tregs in vivo, and the suppression of both primary and secondary antibody responses in preclinical mouse models of allergy [20, 21]
Summary
Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive destruction of pancreatic β cells by diabetogenic CD4+ and CD8+ T cells and B cells, which have loss of immunological tolerance and react with defined islet proteins, such as insulin [1]. If an antigen-specific therapy is effective, the treatment could stop further destruction of insulinproducing cells by restoring immune tolerance without impairing the normal immunity; it is recognized as a primary therapy for preventing the onset or reversal of T1D. The manipulation of Tregs, especially autoantigen-specific Tregs, is considered a promising treatment for T1D [10] because it has a high potential to restore immune tolerance by antigendependent accumulation in draining lymph nodes and inflamed islets [11] and local bystander suppression of other islet-infiltrating pathogenic cells [12], without impairing beneficial immune responses. We have previously reported that a novel liposomal formulation carrying an antigenic polypeptide and α-galactosylceramide (α-GalCer), an activator of invariant natural killer T (iNKT) cells, induced the antigen-specific Tregs in vivo, and the suppression of both primary and secondary antibody responses in preclinical mouse models of allergy [20, 21]
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