Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/10393
Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.
Braza, Mounia S | van Leent, Mandy M T | Lameijer, Marnix | Sanchez-Gaytan, Brenda L | Arts, Rob J W | Perez-Medina, Carlos CNIC | Gonzalez-Perez, Maria ISCIII | Brahmachary, Manisha | Fay, Francois | Kluza, Ewelina | Kossatz, Susanne | Dress, Regine J | Salem, Fadi | Rialdi, Alexander | Reiner, Thomas | Boros, Peter | Strijkers, Gustav J | Calcagno, Claudia C | Ginhoux, Florent | Marazzi, Ivan | Lutgens, Esther | Nicolaes, Gerry A F | Weber, Christian | Swirski, Filip K | Nahrendorf, Matthias | Fisher, Edward A | Duivenvoorden, Raphaël | Fayad, Zahi A | Netea, Mihai G | Mulder, Willem J M | Cano-Ochando, Jordi ISCIII | Conde-San Román, Patricia ISCIII | Rodriguez-Garcia, Mercedes ISCIII
Immunity . 2018 Nov 20;49(5):819-828.e6.
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.
Immunosuppression | Organ Transplantation | Allografts | Animals | Biomarkers | Graft Survival | HMGB1 Protein | Immune Tolerance | Immunity, Innate | Immunologic Memory | Inflammation | Macrophages | Mice | Myeloid Cells | TOR Serine-Threonine Kinases | Vimentin
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