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Nanotherapy that prevents trained immunity and promotes tolerance
Jordi Ochando*1, Willem JM Mulder2
Author Affiliations
1,2Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine, 1470 Madison Avenue, 5th floor, Rm S5-113, New York, USA
Correspondence: Dr. Jordi Ochando
IJIR. 2019;(3)1:WW1 DOI: 10.15305/ijir/v3i1/287
Submitted: 17 December 2018, Accepted: 25 December 2018, Published: 31 January 2019
© IJIR
Investigators at the Icahn School of Medicine at Mount Sinai in New York, USA reported a novel nanoimmunotherapy that targets myeloid cells in vivo in the November 2018 issue of the journal Immunity. Senior authors Drs. Jordi Ochando and Willem Mulder spearheaded an extensive effort in which this nanoimmunotherapy was applied to an experimental mouse model of organ transplantation. Using a short-term regimen, long-term acceptance of the transplanted organ was achieved in the absence of serious side effects.1
The nanomimmunotherapy consisted of high-density lipoprotein (HDL) nanobiologics, which they previously reported to specifically target myeloid cells in vivo.2 In the current study, the authors demonstrate that HDL-nanobiologics target myeloid cells in the heart allograft and myeloid cell precursors in the bone marrow of transplant recipient mice. The latter characteristic of HDL-nanobiologics is critical for the long-term efficacy. The authors hypothesize that myeloid precursors in the bone marrow, such as MDP and CDP, are deactivated before they are mobilized into circulation (Fig. 1).
Fig 1: Positron Emission Tomography/Computed Tomography 3D image shows that HDL nanobiologics labeled with Zirconium-89 (89Zr) accumulate in the bone marrow, which is critical for long-term therapeutic effects of HDL nanobiologics
To prevent myeloid cells’ activation after transplantation, an inhibitor of the mammalian target of rapamycin (mTORi) was incorporated into HDL-nanobiologics. The resulting mTORi-HDL nanobiologics were tested for their ability to prevent inflammatory cytokine production of human monocytes, which were activated in vitro with β-glucan and lipopolysaccharide (LPS). The data demonstrate that mTORi-HDL nanobiologics prevented epigenetic rewiring and glycolytic metabolism activation of human monocytes associated with trained immunity.
Trained immunity is a recently discovered functional state of myeloid cells, which is characterized by non-permanent epigenetic and metabolic underlying potent pro-inflammatory responses.3 Drs. Mulder and Ochando demonstrate that the transplanted allograft induces training of graft-infiltrating macrophages. A short-term mTORi-HDL nanoimmunotherapy during the first week after transplantation prevented the development of trained macrophages in the allograft. Remarkably, mTORi-HDL nanobiologics induced the accumulation of regulatory macrophages that prevented CD8+ T cell proliferation and promoted CD4 Treg cell expansion. To enhance therapeutic efficacy, the authors complemented the mTORi-HDL treatment with a CD40-TRAF6 specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation.2 This synergistic nanoimunnotherapy resulted in indefinite allograft survival, without signs of toxicity.
This innovative strategy, focused on preventing trained immunity, is a major advancement in the field and represents a potential clinical treatment for transplant patients. Since there are no clinical treatments that specifically target myeloid cells in vivo, HDL-based nanobiologics that prevent inflammatory innate immune responses provides a framework for developing novel therapies to promote immunological tolerance in other clinical scenarios such as autoimmunity, chronic inflammatory diseases and allergies.
Competing interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
References
1. Braza MS, van Leent MMT, Lameijer M, Sanchez-Gaytan BL, Arts RJW, Pérez-Medina C, et al. Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance. Immunity. 2018 Nov 20;49(5):819-828.e6.
2. Mulder WJM, van Leent MMT, Lameijer M, Fisher EA, Fayad ZA, Pérez-Medina C. High-Density Lipoprotein Nanobiologics for Precision Medicine. Acc Chem Res. 2018 Jan 16;51(1):127–37.
3. Netea MG, Joosten LAB, Latz E, Mills KHG, Natoli G, Stunnenberg HG, et al. Trained immunity: A program of innate immune memory in health and disease. Science. 2016 Apr 22;352(6284):aaf1098.
4. Lameijer M, Binderup T, van Leent MMT, Senders ML, Fay F, Malkus J, et al. Author Correction: Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates. Nature Biomedical Engineering. 2018 Aug 1;2(8):623–623.