Therapeutic administration of Tregitope-Human Albumin Fusion with Insulin Peptides to promote Antigen-Specific Adaptive Tolerance Induction

Anne S. De Groot,William D. Martin,James Robert White,David Serreze,Gail Skowron,Guilhem Richard,Christine Boyle

doi:10.1038/s41598-019-52331-1

Anne S. De Groot, William D. Martin + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-52331-1

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Abstract

Type 1 Diabetes (T1D) is an autoimmune disease that is associated with effector T cell (Teff) destruction of insulin-producing pancreatic beta-islet cells. Among the therapies being evaluated for T1D is the restoration of regulatory T cell (Treg) activity, specifically directed toward down-modulation of beta-islet antigen-specific T effector cells. This is also known as antigen-specific adaptive tolerance induction for T1D (T1D ASATI). Tregitopes (T regulatory cell epitopes) are natural T cell epitopes derived from immunoglobulin G (IgG) that were identified in 2008 and have been evaluated in several autoimmune disease models. In the T1D ASATI studies presented here, Tregitope peptides were administered to non-obese diabetic (NOD) mice at the onset of diabetes within two clinically-relevant delivery systems (liposomes and in human serum albumin [HSA]-fusion products) in combination with preproinsulin (PPI) target antigen peptides. The combination of Tregitope-albumin fusions and PPI peptides reduced the incidence of severe diabetes and reversed mild diabetes, over 49 days of treatment and observation. Combining HSA-Tregitope fusions with PPI peptides is a promising ASATI approach for therapy of T1D.

Highlights

Type 1 Diabetes (T1D) is an autoimmune disease that is associated with effector T cell (Teff) destruction of insulin-producing pancreatic beta-islet cells
We previously demonstrated that Tregitope peptides co-administered with preproinsulin (PPI) peptides (T1D-Antigen-specific adaptive tolerance induction (ASATI)) could prevent and treat diabetes in non-obese diabetic (NOD) mice[18]
After demonstrating that Human serum albumin (HSA)-Tregitope fusions were non-toxic, as compared to the well-established toxicity of HSA in NOD mice, we show that the combination of Tregitope-HSA fusions and PPI peptides reduce the incidence of severe diabetes and reverses mild diabetes, over the course of 49 days of treatment and observation

Summary

Introduction

Type 1 Diabetes (T1D) is an autoimmune disease that is associated with effector T cell (Teff) destruction of insulin-producing pancreatic beta-islet cells. Among the therapies being evaluated for T1D is the restoration of Treg activity, directed toward down-modulation of beta-islet antigen-specific T effector cells. Non-specific tolerance induction may have off-target effects or may be too weak to rescue and preserve pancreatic islet cells. Targeting regulatory T cell activity to the islet antigens may improve both the efficacy and specificity of Treg treatment for T1D. Tregs regulate immune responses to disease-specific antigens in the peripheral circulation[4]. Both adaptive and natural (nTregs) are activated by antigen-specific epitopes binding to the T cell receptor (TCR), down-modulating the T effector cell response to that same antigen. Development of B9-23 became more complicated when prolonged administration of the peptide induced anaphylaxis in NOD mice[11]; subsequent studies of this peptide suggest that the peptide-MHC binding is somewhat unstable and that the effect of the peptide depends on extrinsic factors[12]

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