# Proinsulin-Loaded Nanoparticles Suppress Insulitis and Induce Temporary Diabetes Remission

## TL;DR

Ultrasmall nanoparticles loaded with proinsulin and ITE can temporarily reverse autoimmune diabetes in mice by reducing immune cell infiltration and promoting regulatory immune responses.

## Contribution

The study introduces a novel nanoparticle-based therapy that induces diabetes remission and highlights the role of regulatory B cells in this process.

## Key findings

- Nanoparticle treatment rapidly reduces insulitis by depleting CD8+ T cells and dendritic cells.
- Treatment induces B cells to produce IL-10, suggesting a role for regulatory B cells in the therapeutic effect.
- Rare cases of durable remission are associated with Foxp3+ regulatory T cells and IFN-γ-producing memory T cells.

## Abstract

What are the main findings?
Ultrasmall iron oxide nanoparticles loaded with proinsulin and the aryl hydrocarbon receptor ligand ITE can induce temporary or, rarely, lasting remission of overt autoimmune diabetes in the model of non-obese diabetic mice.Nanoparticle treatment induces a rapid attenuation of insulitis with marked depletion of CD8+ T cells and dendritic cells.

Ultrasmall iron oxide nanoparticles loaded with proinsulin and the aryl hydrocarbon receptor ligand ITE can induce temporary or, rarely, lasting remission of overt autoimmune diabetes in the model of non-obese diabetic mice.

Nanoparticle treatment induces a rapid attenuation of insulitis with marked depletion of CD8+ T cells and dendritic cells.

What are the implications of the main findings?
Short-term induction of B cells producing IL-10 upon treatment with nanoparticles suggests that the emergence of regulatory B cells may contribute to a therapeutic effect.Proinsulin/ITE ultrasmall nanoparticles may have potential as immunotherapy when combined with complementary approaches promoting long-term restitution of immune tolerance.

Short-term induction of B cells producing IL-10 upon treatment with nanoparticles suggests that the emergence of regulatory B cells may contribute to a therapeutic effect.

Proinsulin/ITE ultrasmall nanoparticles may have potential as immunotherapy when combined with complementary approaches promoting long-term restitution of immune tolerance.

Autoimmune type 1 diabetes (T1D) results from the failure of the physiologic regulatory mechanisms that are designed to maintain immune tolerance to pancreatic beta cells. Consequently, the design of strategies to restore tolerance to beta cell antigens is an attractive objective of translational research. We have designed ultrasmall nanoparticles (NPs) loaded with a proinsulin (PI) fusion protein and an agonist for the aryl hydrocarbon receptor (AhR), a transcription factor promoting tolerance induction by different immune cells. We report that a 4 week-treatment with these NPs in non-obese diabetic (NOD) mice starting at disease onset induces temporary and sometimes durable disease remission. Mechanistically, short-term NP treatment induces a rapid depletion of islet infiltrates with a dramatic reduction in the number of CD8+ T cells and dendritic cells. This is accompanied by the emergence of B lymphocytes producing IL-10. In the rare mice that undergo durable disease remission, the disappearance of islet infiltrates is associated with the emergence of Foxp3+ CD4+ regulatory T cells, IFN-γ-producing memory T cells in the spleen, and draining lymph nodes (LNs). We conclude that treatment with these NPs could be of interest in the treatment of recent-onset autoimmune diabetes, but is unlikely to be sufficient for the induction of long-term remission as a stand-alone therapy.