Dual-Sized Microparticle System for Generating Suppressive Dendritic Cells Prevents and Reverses Type 1 Diabetes in the Nonobese Diabetic Mouse Model

Abstract

Antigen specificity is a primary goal in developing curative therapies for autoimmune disease. Dendritic cells (DCs), as the most effective antigen presenting cells in the body, represent a key target to mediate restoration of antigen-specific immune regulation. Here, we describe an injectable, dual-sized microparticle (MP) approach that employs phagocytosable ∼1 μm and nonphagocytosable ∼30 μm MPs to deliver tolerance-promoting factors both intracellularly and extracellularly, as well as the type 1 diabetes autoantigen, insulin, to DCs for reprogramming of immune responses and remediation of autoimmunity. This poly­(lactic-co-glycolic acid) (PLGA) MP system prevented diabetes onset in 60% of nonobese diabetic (NOD) mice when administered subcutaneously in 8 week old mice. Prevention of disease was dependent upon antigen inclusion and required encapsulation of factors in MPs. Moreover, administration of this “suppressive-vaccine” boosted pancreatic lymph node and splenic regulatory T cells (Tregs), upregulated PD-1 on CD4+ and CD8+ T cells, and reversed hyperglycemia for up to 100 days in recent-onset NOD mice. Our results demonstrate that a MP-based platform can reeducate the immune system in an antigen-specific manner, augment immunomodulation compared to soluble administration of drugs, and provide a promising alternative to systemic immunosuppression for autoimmunity.

Nano and Microparticle Emerging Strategies for Treatment of Autoimmune Diseases: Multiple Sclerosis and Type 1 Diabetes

“…[ 91 ] A modification of this system increased the amounts of TGF‐ β and GM‐CSF and used denatured insulin as antigen (Table 1). [ 92 ] Encapsulation, antigen, tolerogenic, and recruitment factors were all required, otherwise the treatment was no longer effective. When the new formulation was administered weekly via subcutaneous injection, for 3 weeks, followed by four monthly booster injections, it was able to delay T1D onset in 8‐week‐old NOD mice, with 60% of mice remaining diabetes‐free.…”

“…When the new formulation was administered weekly via subcutaneous injection, for 3 weeks, followed by four monthly booster injections, it was able to delay T1D onset in 8‐week‐old NOD mice, with 60% of mice remaining diabetes‐free. [ 92 ] This delay in onset was associated with increased PD‐1 on CD4 + and CD8 + T cells as well as an increase in CD11b + CD11c + DCs in the draining lymph nodes. Additionally, three subcutaneous administrations during the week of onset, followed by weekly booster injections for three weeks, temporarily reversed T1D in recent onset diabetes, for up to 100 days.…”

“…Additionally, three subcutaneous administrations during the week of onset, followed by weekly booster injections for three weeks, temporarily reversed T1D in recent onset diabetes, for up to 100 days. [ 92 ]…”

Immunomodulatory Dual-Sized Microparticle System Conditions Human Antigen Presenting Cells Into a Tolerogenic Phenotype In Vitro and Inhibits Type 1 Diabetes-Specific Autoreactive T Cell Responses

“…The field has called for the use of combination therapies as a potentially more effective strategy to augment T cell targeted agents (15)(16)(17)(18)(19). To address this, we developed a novel biomaterial therapy to deliver immunomodulatory agents along with autoantigen as a means to recruit and tolerize dendritic cells (DCs) for robust antigen-specific T cell tolerance (20,21). Here, we extensively characterized human immune cell responses in vitro as an important bridge to clinical translation for this novel dual sized microparticle (dMP) formulation.…”

“…This carefully selected combination of tolerogenic agents and disease-relevant autoantigen, delivered via PLGA MP encapsulation for subcutaneous injection, has been tested in two murine models of antigen-specific autoimmunity. This therapy successfully prevented diabetes in NOD mice and reduced disease severity in an early treatment model of experimental autoimmune encephalomyelitis (EAE) (21,51). Often, efficacy in mouse models does not scale to trials in human subjects, highlighting the need for in vitro preclinical assays to test dose-response in target cells, as well as off-target or unexpected effects (52).…”