Impact of antigen loading in tolerogenic nanoparticles to mitigate Th2-mediated allergic lung inflammation.

IF 5.7 3区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Drug Delivery and Translational Research Pub Date : 2024-10-01 Epub Date: 2024-06-11 DOI:10.1007/s13346-024-01632-8
Brianna L Scotland, Shruti Dharmaraj, Andrea L Cottingham, Nhu Truong, Svetlana P Chapoval, Achsah D Keegan, Ryan M Pearson
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Abstract

Allergic disease is a major global health concern that imposes significant life-altering and economic burdens on affected individuals. However, there is still no cure. Polymer-based nanoparticles (NP) have shown the potential to induce antigen (Ag)-specific immune tolerance in various Th1/17 and Th2-mediated immune disorders including autoimmunity and allergy. Common methods by which Ags are associated with NPs are through surface conjugation or encapsulation. However, these Ag delivery strategies can be associated with several caveats that dampen their effectiveness such as uncontrolled Ag loading, a high Ag burst release, and an increased immune recognition profile. We previously developed Ag-polymer conjugate NPs (acNPs) to overcome those noted limitations, while allowing for controlled delivery of precise quantities of Ag to innate immune cells for Ag-specific CD4 T cell modulation. Here, we utilized ovalbumin (OVA) protein-poly(lactic-co-glycolic acid) (PLGA) conjugate NPs (acNP-OVA) to elucidate the impact of Ag loading on the induction of Th2 tolerance using a prophylactic and therapeutic OVA/ALUM-induced mouse model of allergic lung inflammation (ALI) in comparison to Ag-encapsulated PLGA NPs (NP(Ag)). We demonstrate that acNP-OVA formulations reduced OVA-specific IgE and inhibited Th2 cytokine secretions in an Ag loading-dependent manner when administered prophylactically. Administration of acNP-OVA to pre-sensitized mice did not affect OVA-specific IgE and Th2 cytokines tended to be reduced, however, there was no clear Ag loading dependency. acNP-OVA with medium-to-low Ag loadings were well tolerated, while formulations with high Ag loadings, including NP(Ag) resulted in anaphylaxis. Overall, our results clarify the relationship between Ag loading and Ag-specific IgE and Th2 cytokine responses in a murine model of ALI, which provides insight useful for future design of tolerogenic NP-based immunotherapies.

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耐受性纳米粒子中的抗原负载对减轻 Th2 介导的过敏性肺部炎症的影响。
过敏性疾病是全球关注的重大健康问题,给患者带来了严重的生活和经济负担。然而,目前仍无特效药。基于聚合物的纳米粒子(NP)已显示出诱导抗原(Ag)特异性免疫耐受的潜力,可治疗各种 Th1/17 和 Th2 介导的免疫疾病,包括自身免疫和过敏。将抗原与 NPs 结合的常见方法是通过表面共轭或封装。然而,这些银离子递送策略可能会有一些影响其有效性的注意事项,如银离子负载不可控、银离子猝发释放率高以及免疫识别率增加等。我们以前开发的 Ag 聚合物共轭 NPs(acNPs)克服了上述局限性,同时还能控制向先天性免疫细胞递送精确数量的 Ag,以实现 Ag 特异性 CD4 T 细胞调控。在这里,我们利用卵清蛋白(OVA)蛋白-聚(乳酸-共聚乙醇酸)(PLGA)共轭 NPs(acNP-OVA),使用预防性和治疗性 OVA/ALUM 诱导的过敏性肺炎症(ALI)小鼠模型,与包裹 Ag 的 PLGA NPs(NP(Ag))相比,阐明了 Ag 负载对诱导 Th2 耐受的影响。我们的研究表明,在预防性给药时,acNP-OVA制剂可降低OVA特异性IgE,并以Ag负载依赖性方式抑制Th2细胞因子分泌。给预先致敏的小鼠施用 acNP-OVA 不会影响 OVA 特异性 IgE,Th2 细胞因子也有减少的趋势,但并不存在明显的 Ag 负载依赖性。总之,我们的研究结果阐明了在小鼠 ALI 模型中Ag 负载与Ag 特异性 IgE 和 Th2 细胞因子反应之间的关系,为今后设计基于 NP 的耐受性免疫疗法提供了有益的启示。
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来源期刊
Drug Delivery and Translational Research
Drug Delivery and Translational Research MEDICINE, RESEARCH & EXPERIMENTALPHARMACOL-PHARMACOLOGY & PHARMACY
CiteScore
11.70
自引率
1.90%
发文量
160
期刊介绍: The journal provides a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. Rationally developed, effective delivery systems can potentially affect clinical outcome in different disease conditions. Research focused on the following areas of translational drug delivery research will be considered for publication in the journal. Designing and developing novel drug delivery systems, with a focus on their application to disease conditions; Preclinical and clinical data related to drug delivery systems; Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes Short-term and long-term biocompatibility of drug delivery systems, host response; Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering; Image-guided drug therapy, Nanomedicine; Devices for drug delivery and drug/device combination products. In addition to original full-length papers, communications, and reviews, the journal includes editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of the Controlled Release Society.
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