Controlled delivery of a metabolic modulator promotes regulatory T cells and restrains autoimmunity


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Abstract

Autoimmune disorders occur when the immune system abnormally recognizes and attacks self-molecules. Dendritic cells (DCs) play a powerful role in initiating adaptive immune response, and are therefore a recent target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a small molecule glutamate receptor enhancer, alters how DCs metabolize glutamate, skewing cytokine secretion to bias T cell function. These effects provide protection in mouse models of multiple sclerosis (MS) by polarizing T cells away from inflammatory TH17 cells and toward regulatory T cells (TREG) when mice receive daily systemic injections of PHCCC. However, frequent, continued treatment is required to generate and maintain therapeutic benefits. Thus, the use of PHCCC is limited by poor solubility, the need for frequent dosing, and cell toxicity. We hypothesized that controlled release of PHCCC from degradable nanoparticles (NPs) might address these challenges by altering DC function to maintain efficacy with reduced treatment frequency and toxicity. This idea could serve as a new strategy for harnessing biomaterials to polarize immune function through controlled delivery of metabolic modulators. PHCCC was readily encapsulated in nanoparticles, with controlled release of 89% of drug into media over three days. Culture of primary DCs or DC and T cell co-cultures with PHCCC NPs reduced DC activation and secretion of pro-inflammatory cytokines, while shifting T cells away from TH17 and toward TREG phenotypes. Importantly, PHCCC delivered to cells in NPs was 36-fold less toxic compared with soluble PHCCC. Treatment of mice with PHCCC NPs every three days delayed disease onset and decreased disease severity compared with mice treated with soluble drug at the same dose and frequency. These results highlight the potential to promote tolerance through controlled delivery of metabolic modulators that alter DC signaling to polarize T cells, and suggest future gains that could be realized by engineering materials that provide longer term release.

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