Abstract
Autoreactive T cells are thought to orchestrate the onset and progression of autoimmune diabetes. Key cognate antigens of these diabetogenic T cells include hybrid insulin peptides, formed by the fusion of insulin fragments to cleavage products of other β-cell granule proteins. Here we review initial work exploring tolerance induction to a hybrid insulin peptide using a biodegradable, nanoparticle delivery system in non-obese diabetic (NOD) mice. The immune phenotype(s) and possible mechanism(s) behind antigen-specific tolerance induction were dissected with a disease transfer model using transgenic autoreactive mouse T cells. Treatment of NOD mice with peptide-coupled nanoparticles appeared to have a dual function in preventing diabetes onset, inducing anergy in effector T cells and enhancing the activity of regulatory T cells. Importantly, the ratio of these two cell types in the pancreas was pushed toward tolerance. Antigen-specific tolerance induction to hybrid insulin peptides has the translational potential to preserve islet β-cells in new-onset or at-risk patients and prevent recurrent autoimmunity in transplant patients.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β-cells in the pancreatic islets are destroyed, resulting in hyperglycemia
Autoreactive T cells directed toward islet antigens play an important role in this process, entering the pancreas at an early stage and contributing substantially to the infiltration of immune cells in the islets or insulitis [1,2,3,4]
A variety of approaches and efforts over many years were applied to identify T cell antigens and a combination of biochemical and mass spectrometric techniques led to the identification of chromogranin A (ChgA) and islet amyloid polypeptide (IAPP) as potential sources of the peptide ligands for several of the BDC T cell clones [10]
Summary
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β-cells in the pancreatic islets are destroyed, resulting in hyperglycemia. Autoreactive T cells directed toward islet antigens play an important role in this process, entering the pancreas at an early stage and contributing substantially to the infiltration of immune cells in the islets or insulitis [1,2,3,4]. The only available ongoing treatment on a cost-effective and reasonable basis for most patients is insulin replacement therapy; complications such as kidney and vascular disease still occur in treated patients. Even with important advances in islet transplantation and strategies for inducing tolerance to grafts, recurrent immune activation to βcells is a major hurdle in long-term islet graft survival. Novel therapeutic approaches that can arrest disease onset or aid islet transplantation without the need for broad immunosuppression are under intense investigation. We discuss recent advances in the use of nanoparticle antigen transport as a viable approach for effective long-term treatment of T1D
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