Antigen and Epitope Delivering Nanoparticles Targeting Liver Induce Comparable Immunotolerance in Allergic Airway Disease and Anaphylaxis as Nanoparticles Delivering Pharmaceuticals

• Published in: ACS nano 2020-12, Vol.15 (1), p.1608-1626
• Main Authors: Liu, Qi, Wang, Xiang, Liu, Xiangsheng, Liao, Yu-Pei, Chang, Chong Hyun, Mei, Kuo-Ching, Jiang, Jinhong, Tseng, Shannon, Gochman, Grant, Huang, Marissa, Thatcher, Zoe, Li, Jiulong, Allen, Sean D., Lucido, Luke, Xia, Tian, Nel, Andre E.
• Format: Article
• Language: English
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.0c09206

The targeting of natural tolerogenic liver sinusoidal endothelial cells (LSEC) by nanoparticles (NPs), decorated with a stabilin receptor ligand, is capable of generating regulatory T-cells (Tregs), which can suppress antigen-specific immune responses, including to ovalbumin (OVA), a possible food allergen. In this regard, we have previously demonstrated that OVA-encapsulating PLGA nanoparticles eliminate allergic airway inflammation in OVA-sensitized mice, prophylactically and therapeutically. A competing approach is a nanocarrier platform that incorporates pharmaceutical agents interfering in mTOR (rapamycin) or NF-κB (curcumin) pathways, with the ability to induce a tolerogenic state in non-targeted antigen-presenting cells (APC) system-wide. First, we compared OVA-encapsulating, LSEC-targeting tolerogenic nanoparticles (TNPs) with non-targeted NPs incorporating curcumin and rapamycin (Rapa) in a murine eosinophilic airway inflammation model, which is Treg sensitive. This demonstrated roughly similar tolerogenic effects on allergic airway inflammation by stabilin-targeting NP OVA vs . non-targeted NPs delivering OVA plus Rapa. Reduction in eosinophilic inflammation and TH2-mediated immune responses in the lung were accompanied by increased Foxp3 + Treg recruitment and TGF-β production in both platforms. Since OVA incorporates IgE-binding as well as non-IgE binding epitopes, the next experiment explored the possibility of obtaining immune tolerance by non-anaphylactic T-cell epitopes. This was accomplished by incorporating OVA 323-339 and OVA 257-264 epitopes in liver-targeting NP to assess the prophylactic and therapeutic impact on allergic inflammation in transgenic OT-II mice. Importantly, we demonstrated that the MHC-II binding (former) but not the MHC-I binding (latter) epitope interfered in allergic airway inflammation, improving TNP OVA efficacy. The epitope-specific effect was transduced by TGF-β producing Tregs. In the final phase of experimentation, we used an OVA-induced anaphylaxis model to demonstrate that targeted delivery of OVA and its MHC-II epitope could significantly suppress the anaphylaxis symptom score, mast cell release, and the late-phase inflammatory response. In summary, these results demonstrate comparable efficacy of LSEC-targeting vs . pharmaceutical PLGA nanoparticles, as well as the ability of T-cell epitopes to achieve similar response outcomes as the intact allergens.