Inhibiting inflammation with myeloid cell-specific nanobiologics promotes organ transplant acceptance Journal Article
| Authors: | Braza, M. S.; van Leent, M. M. T.; Lameijer, M.; Sanchez-Gaytan, B. L.; Arts, R. J. W.; Pérez-Medina, C.; Conde, P.; Garcia, M. R.; Gonzalez-Perez, M.; Brahmachary, M.; Fay, F.; Kluza, E.; Kossatz, S.; Dress, R. J.; Salem, F.; Rialdi, A.; Reiner, T.; Boros, P.; Strijkers, G. J.; Calcagno, C. C.; Ginhoux, F.; Marazzi, I.; Lutgens, E.; Nicolaes, G. A. F.; Weber, C.; Swirski, F. K.; Nahrendorf, M.; Fisher, E. A.; Duivenvoorden, R.; Fayad, Z. A.; Netea, M. G.; Mulder, W. J. M.; Ochando, J. |
| Article Title: | Inhibiting inflammation with myeloid cell-specific nanobiologics promotes organ transplant acceptance |
| Abstract: | Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance. An unresolved problem in organ transplantation is to establish graft acceptance in the absence of long-term immunosuppressive therapy. Braza et al. unravel important molecular mechanisms underlying myeloid cell activation in an experimental organ transplantation model and develop a combined nanoimmunotherapy that targets myeloid cells in hematopoietic organs and the allograft. Short-term nanobiologic immunotherapy prevents inflammation and induces indefinite allograft survival. © 2018 Elsevier Inc. |
| Keywords: | transplantation; immunotherapy; mtor; cd40; traf6; innate immune memory; nanoimmunotherapy; trained immunity |
| Journal Title: | Immunity |
| Volume: | 49 |
| Issue: | 5 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2018-11-20 |
| Start Page: | 819 |
| End Page: | 828.e6 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2018.09.008 |
| PUBMED: | 30413362 |
| PROVIDER: | scopus |
| PMCID: | PMC6251711 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 December 2018 -- Source: Scopus |
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