3 research outputs found
Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.
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.We thank M. Jaeger (Radboudumc) for kindly providing flourescein
isothiocyanate-labelled Candida albicans. D. Williams (East
Tennessee State University) provided the β-glucan we used in our
initial experiments. H. Lemmers (Radboudumc) kindly prepared the
purified lipopolysaccharide used for stimulation of primary human
monocytes and macrophages. Part of the figures were prepared
using (among other software) Biorender.com. B.N. is supported
by a National Health and Medical Research Council (Australia)
Investigator Grant (APP1173314). This work was supported by
National Institutes of Health grants R01 HL144072, R01 CA220234
and P01 HL131478, as well as a Vici grant from the Dutch Research
Council NWO and an ERC Advanced Grant (all to W.J.M.M.). M.G.N.
was supported by a Spinoza grant from Dutch Research Council
NWO and an ERC Advanced Grant (#833247).S
Nanoengineering Apolipoprotein A1-Based Immunotherapeutics
In the slipstream of targeting the adaptive immune system, innate immunotherapy strategies are being developed. In this context, technologies based on natural carrier vehicles that inherently interact with the innate immune system, are increasingly being considered. Immunoregulatory nanotherapeutics based on natural apolipoprotein A1 (apoA1) are discussed here. This protein is a helical, amphipathic macromolecule and the main constituent of high-density lipoprotein. In that capacity, apoA1 interacts specifically with innate immune cells, such as monocytes and macrophages, to collect and transport lipophilicmolecules throughout the body. Exactly these unique features make apoA1 a compelling elementary constituent of biocompatible self-assembled nanotherapeutics. Such apoA1-based nanotherapeutics (A1-nanotherapeutics) can be engineered and functionalized to induce or mitigate an innate immune response or to orchestrate an adaptive immune response through antigen delivery to dendritic cells. The authors first discuss apoA1's properties and how these can be exploited to generate libraries of A1-nanotherapeutics using advanced manufacturing approaches such as microfluidics or continuous flow methods. Using high-throughput in vitro screening methods and in vivo imagingto identify promising formulations are then recommend. Finally, Three distinct immunotherapy strategies are proposed to effectively treat a variety of diseases—including cancer, infection, and cardiovascular disease—and promote allograft survival in transplantation
Nanoengineering Apolipoprotein A1-Based Immunotherapeutics
In the slipstream of targeting the adaptive immune system, innate immunotherapy strategies are being developed. In this context, technologies based on natural carrier vehicles that inherently interact with the innate immune system, are increasingly being considered. Immunoregulatory nanotherapeutics based on natural apolipoprotein A1 (apoA1) are discussed here. This protein is a helical, amphipathic macromolecule and the main constituent of high-density lipoprotein. In that capacity, apoA1 interacts specifically with innate immune cells, such as monocytes and macrophages, to collect and transport lipophilicmolecules throughout the body. Exactly these unique features make apoA1 a compelling elementary constituent of biocompatible self-assembled nanotherapeutics. Such apoA1-based nanotherapeutics (A1-nanotherapeutics) can be engineered and functionalized to induce or mitigate an innate immune response or to orchestrate an adaptive immune response through antigen delivery to dendritic cells. The authors first discuss apoA1's properties and how these can be exploited to generate libraries of A1-nanotherapeutics using advanced manufacturing approaches such as microfluidics or continuous flow methods. Using high-throughput in vitro screening methods and in vivo imagingto identify promising formulations are then recommend. Finally, Three distinct immunotherapy strategies are proposed to effectively treat a variety of diseases—including cancer, infection, and cardiovascular disease—and promote allograft survival in transplantation