A Chromatin-Mimetic Nanomedicine for Therapeutic Tolerance Induction

被引：12

作者：

Li, Bowen ^{[1
]}

Yuan, Zhefan ^{[2
]}

McMullen, Patrick ^{[2
]}

Xie, Jingyi ^{[1
]}

Jain, Priyesh ^{[2
]}

Hung, Hsiang-Chieh ^{[2
]}

Xu, Shihan ^{[1
]}

Zhang, Peng ^{[2
]}

Lin, Xiaojie ^{[2
]}

Wu, Kan ^{[2
]}

Jiang, Shaoyi ^{[1
,2
]}

机构：

[1] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA

[2] Univ Washington, Dept Chem Engn, Seattle, WA 98195 USA

来源：

ACS NANO | 2018年 / 12卷 / 12期

关键词：

GpG; immune tolerance; immunogenicity; immunosuppression; anti-PEG antibody; DYING CELLS; RAPAMYCIN TOXICITY; AUTOIMMUNE; EFFICACY; IMMUNOGENICITY; VACCINATION; INHIBITION; DELIVERY;

D O I：

10.1021/acsnano.8b04314

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The undesirable immune response poses a life-threatening challenge to human health. It not only deteriorates the therapeutic performance of biologic drugs but also contributes to various diseases such as allergies and autoimmune diseases. Inspired by the role of chromatin in the maintenance of natural immune tolerance, here we report a DNA-protein polymeric nanocomplex that can mimic the tolerogenic function of chromatin and induce an immune tolerance to its protein cargos. We first proved that the chromatin-mimetic nanomedicine loaded with keyhole limpet hemocyanin (KLH), a highly immunogenic model protein, could elicit a durable antigen-specific immune tolerance to KLH lasting for at least five weeks in mice. Following the proof-of-concept study, we demonstrated that this nanomedicine could be applied to improve the safety and efficacy of a biologic drug, PEGylated uricase, by attenuating the relevant antibody (Ab) responses. Moreover, we also demonstrated that prophylactic treatments with this nanomedicine could tolerize the immune system with the allergen of ovalbumin (OVA) and thus inhibit the occurrence of airway inflammation in an OVA-induced allergic asthma murine model. Collectively, our work illustrates a nature-inspired concept of immune tolerance induction and establishes a useful tool to specifically suppress unwanted immune responses for therapeutic purposes.

引用

页码：12004 / 12014

页数：11

共 58 条

[1]

ABUCHOWSKI A, 1977, J BIOL CHEM, V252, P3578

[2] Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2) [J].