The virtue of tolerance

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Science Translational Medicine  05 Dec 2018:
Vol. 10, Issue 470, eaaw0521
DOI: 10.1126/scitranslmed.aaw0521


A chromatin-inspired nanodrug suppresses undesired immune responses.

The immune system protects us from environmental threats such as pathogens. However, it can sometimes overreact and lead to unwanted consequences, such as allergic reactions or autoimmunity. Moreover, biologic drugs administered as therapy can become targeted by the immune system. It is challenging to specifically blunt such responses without compromising overall immunity. Chromatin, a natural DNA-protein complex, can drive immune tolerance. Here, Li et al. developed a nanocomplex that mimics the tolerogenic function of chromatin to induce immune tolerance in a highly antigen-specific manner.

To produce the nanocomplex, the authors electrostatically assembled protein cargo with a short DNA sequence reported to be tolerogenic. The two are then wrapped in a thin shell of polymer network for delivery under physiological conditions. Upon ingestion by the immune cells that process antigens, the polymer scaffold is shredded by the acidic environment, releasing the DNA and protein cargo inside the cell. This leads to a cascade of regulatory responses that promote the differentiation of antigen-specific, tolerogenic adaptive immune cells. The authors first confirmed that the nanocomplex has the desired size and surface charge that allows for their delivery into the right compartments in the antigen-processing cells without killing the cells. They also varied the formulation of the nanocomplex to achieve favorable stability and degradability. The researchers then carried out studies in mice to demonstrate the efficacy of the nanocomplex in inducing sustainable immune suppression in vivo. As a proof of concept, they first showed that the nanocomplex resulted in durable suppression of antibody responses toward a highly immunogenic model protein. Next, the authors examined whether the nanocomplex can address the immunogenicity of biologic drugs. They showed that the nanocomplex dramatically reduced the level of antibody against an enzyme drug, as well as an anchoring polymer commonly used in biologic drugs. Lastly, the authors further demonstrated that the nanocomplex can evoke immune tolerance in an allergic asthma model. Pretreatment with the nanocomplex significantly reduced level of the allergy-mediating antibody and airway inflammation in mice. Although more studies are needed to understand the molecular determinants of the efficacy and the compatibility of the platform with other protein cargos, the results shown here have demonstrated promise of the biomimetic design for dampening the immune system.

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