Abstract

Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.

Results from nanoScan® PET/CT

• radiolabelled the protein component of four different IL4 therapeutics, namely, bare IL4, the bare apoA1–IL4 fusion protein and discoidal and spherical IL4-aNPs, with zirconium-89 (⁸⁹Zr)
• 24 h post intravenous administration showed that ⁸⁹Zr-IL4 and ⁸⁹Zr-apoA1–IL4 accumulated mostly in the kidney and liver
• ⁸⁹Zr-IL4-aNPs accumulated in relatively higher amounts in immune-cell-rich organs, including the spleen and bone marrow (Fig 5a)

Fig. 5 a, PET-CT render at 24 h after injecting ⁸⁹Zr-labelled constructs. b, ⁸⁹Zr-labelled construct blood half-life (n = 5, as fitted with a two-phase decay function). ID, injected dose. c, Ex vivo gamma counting of tissues 24 h after ⁸⁹Zr-labelled construct injection (n = 5), number represents ratio target to clearance organs. d, Cell type-specific biodistribution of DiO-labelled discoid IL4-aNPs in spleen and bone marrow, as measured by flow cytometry. e, ⁸⁹Zr-IL4-aNP blood half-life in non-human primates. f, Organ SUV mean over time in ⁸⁹Zr-IL4-aNPs-injected non-human primates (n = 2). g, Organ-specific SUV mean 48 h after ⁸⁹Zr-IL4-aNPs injection in non-human primates (n = 2). h, PET-MRI scan of non-human primate 48 h after ⁸⁹Zr-IL4-aNPs injection. Data are presented as mean ± s.d. where appropriate. DIO, 3,3′-dioctadecyloxacarbocyanine perchlorate; MFI, mean fluorescence intensity; NHP, non-human primate.

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