Arrest in the Progression of Type 1 Diabetes at the Mid-Stage of Insulitic Autoimmunity Using an Autoantigen-Decorated All-trans Retinoic Acid and Transforming Growth Factor Beta-1 Single Microparticle Formulation.

Brett E. Phillips,Wilson S. Meng,Yesica Garciafigueroa,Carl Engman,Robert J. Lakomy,Wen Liu,Nick Giannoukakis,Massimo Trucco,Yiwei Wang

doi:10.3389/fimmu.2021.586220

Abstract

Type 1 diabetes (T1D) is a disorder of impaired glucoregulation due to lymphocyte-driven pancreatic autoimmunity. Mobilizing dendritic cells (DC) in vivo to acquire tolerogenic activity is an attractive therapeutic approach as it results in multiple and overlapping immunosuppressive mechanisms. Delivery of agents that can achieve this, in the form of micro/nanoparticles, has successfully prevented a number of autoimmune conditions in vivo. Most of these formulations, however, do not establish multiple layers of immunoregulation. all-trans retinoic acid (RA) together with transforming growth factor beta 1 (TGFβ1), in contrast, has been shown to promote such mechanisms. When delivered in separate nanoparticle vehicles, they successfully prevent the progression of early-onset T1D autoimmunity in vivo. Herein, we show that the approach can be simplified into a single microparticle formulation of RA + TGFβ1 with surface decoration with the T1D-relevant insulin autoantigen. We show that the onset of hyperglycemia is prevented when administered into non-obese diabetic mice that are at the mid-stage of active islet-selective autoimmunity. Unexpectedly, the preventive effects do not seem to be mediated by increased numbers of regulatory T-lymphocytes inside the pancreatic lymph nodes, at least following acute administration of microparticles. Instead, we observed a mild increase in the frequency of regulatory B-lymphocytes inside the mesenteric lymph nodes. These data suggest additional and potentially-novel mechanisms that RA and TGFβ1 could be modulating to prevent progression of mid-stage autoimmunity to overt T1D. Our data further strengthen the rationale to develop RA+TGFβ1-based micro/nanoparticle “vaccines” as possible treatments of pre-symptomatic and new-onset T1D autoimmunity.

Highlights

Type 1 diabetes (T1D) is widely-viewed as a disorder of impaired glucoregulation primarily due to a pancreatic beta (β) cell-selective, largely lymphocyte-driven autoimmunity [1,2,3]
Dead and dying β cells are acquired by macrophages and dendritic cells (DC) in steady-state flux through islet structures which migrate into the pancreatic lymph nodes (PLN) where they amplify a vicious circle of T1D autoimmunity by triggering expansion of more β cell-autoreactive T-cells
That a novel and stable formulation of a retinoic acid (RA) and TGFβ-formulated single microparticle, decorated with a T1D-relevant autoantigen (Insulin B9-23 peptide) [41,42,43,44] can prevent the onset of hyperglycemia when administered into nonobese diabetic (NOD) mice that are at the mid-stage of active islet-selective autoimmunity

Summary

Introduction

Type 1 diabetes (T1D) is widely-viewed as a disorder of impaired glucoregulation primarily due to a pancreatic beta (β) cell-selective, largely lymphocyte-driven autoimmunity [1,2,3]. Regulatory lymphocytes, especially T-cells that stably-express the Foxp transcription factor (Foxp3+ Tregs) prevent autoimmune diabetes in the NOD mouse [9] and there is strong evidence that they can regulate the pool of autoreactive effector CD4+ and CD8+ T-cells in humans [10,11,12]. Autologous Tregs are in different phases of clinical trials to preserve residual beta cell mass in new onset T1D patients [13,14,15,16,17]. A simpler way to generate Tregs in vivo, and fortify other layers of immune tolerance using a “vaccine,” would be decisive in preventing and treating new onset disease

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Results

Conclusion