Identifying Mechanisms Supporting Nanoparticle Therapy for Autoimmune Diseases

Northwestern Medicine scientists in the laboratory of Stephen Miller, PhD, professor emeritus of Microbiology-Immunology, have identified the cellular and molecular mechanisms required for the antigen-specific tolerance inducing abilities of a novel nanoparticle therapy for treating autoimmune diseases, according to a recent study published in Science Advances.

Many autoimmune diseases occur when the immune system, especially autoreactive T-cells, mistakenly targets and attacks healthy cells and tissues. General immunosuppressive therapies, which target the activation, migration and function of these T-cells, are the current standard of care for nearly 100 known autoimmune diseases.

Recent efforts led by the Miller laboratory and others have focused on developing antigen-specific tolerance therapies for autoimmune diseases, which aim to “retrain” the immune system by inhibiting the effector T-cells promoting autoimmunity and inducing regulatory T-cells to prevent autoimmunity.

Miller’s laboratory developed a biodegradable nanoparticle therapy that has been shown to induce an antigen-specific regulatory immune response in mouse models of autoimmune diseases.

In a previous clinical trial, the scientists found this gliadin-containing nanoparticle treatment blocked both intestinal changes and an increase in inflammatory T-cells within the blood following gluten challenge in patients with celiac disease.

In the current study, the scientists aimed to identify the cellular and molecular mechanisms utilized by this novel therapy to induce a regulatory T-cell response.

“We knew that if you inject these nanoparticles into an animal model, the nanoparticles get taken up by antigen presenting cells and this resulted in increased regulatory T-cells and decreased inflammatory disease. However, we did not know how this happens,” said Joseph Podojil, PhD, research associate professor of Microbiology-Immunology and lead author of the study.

Using a combination of tracible nanoparticles, single-cell RNA sequencing and in vitro cultures to analyze cells post nanoparticle therapy, the scientists discovered that myeloid cells — immune cells originating from bone marrow — phagocytose, or break down, the nanoparticle and these cells undergo cell death known as apoptosis, which in turn releases oxidized DNA.

This release of oxidized DNA subsequently triggers activation of the STING pathway, which triggers the release of type-I interferons — cytokines known for driving an inflammatory immune response. However, the data showed that these cytokines also help drive the induction and expansion of regulatory T-cells, as confirmed with in vivo analyses.

“Importantly, this study identified a naturally occurring pathway that our bodies and our immune systems have developed to allow for peripheral self-tolerance, and this therapy has taken advantage of that apoptotic cell clearance pathway mechanism. Consequently, we induce these regulatory T-cell populations that inhibit inflammatory response against a self-antigen and inhibit autoimmune responses in an antigen-specific manner,” Podojil said.

Using cell cultures, the scientists also discovered an increase in anti-inflammatory dendritic cells — specialized immune cells that initiate the immune system by presenting antigens on its surface — which may help drive the regulatory T-cell response.

In the future, Podojil said the team aims to further investigate the functional activity of these dendritic cells and how they interact with regulatory T-cell populations.

“Another one of our next steps is to really delve into this dendritic cell population that’s responsible for inducing the regulatory T-cells and figuring out how that dendritic cell is altering this phenotype,” Podojil said.

The scientists also aim to determine the durability of this induced antigen-specific tolerance response Podojil said.

“Another pressing question is how long the treatment-induced tolerance actually lasts? These studies could help to inform the clinical protocol or treatment schedule for a patient,” Podojil said.

Co-authors include Andrew Cogswell, PhD, research assistant professor of Microbiology-Immunology; Tobias Neef, PhD, research assistant professor of Microbiology-Immunology; Gabriel Arellano Lorca, PhD, research assistant professor of Microbiology-Immunology; Joshua Meeks, ‘03 MD, ‘05 PhD, ‘06, ‘11 GME, the Edward M. Schaeffer, MD, PhD Professor of Urology; and Dan Xu, PhD, research assistant professor of Microbiology-Immunology.

This work was supported by grants from Cour Pharmaceutical Development Company, National Institutes of Health grant R01AI148076, gifts from the Johnnie Walkers MS Foundation, the Amy and David Fulton Foundation, the Crammer Family Foundation, the Thomas and Deige McLaughlin Foundation, the Rottering Family Foundation and a JDRF Postdoctoral Fellowship (3-PDF-2018-582-A-N).