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00925njm 22002777a 4500 dc Braza, Mounia S author van Leent, Mandy M T author Lameijer, Marnix author Sanchez-Gaytan, Brenda L author Arts, Rob J W author Perez-Medina, Carlos author Gonzalez-Perez, Maria author Brahmachary, Manisha author Fay, Francois author Kluza, Ewelina author Kossatz, Susanne author Dress, Regine J author Salem, Fadi author Rialdi, Alexander author Reiner, Thomas author Boros, Peter author Strijkers, Gustav J author Calcagno, Claudia author Ginhoux, Florent author Marazzi, Ivan author Lutgens, Esther author Nicolaes, Gerry A F author Weber, Christian author Swirski, Filip K author Nahrendorf, Matthias author Fisher, Edward A author Duivenvoorden, Raphaël author Fayad, Zahi A author Netea, Mihai G author Mulder, Willem J M author Ochando, Jordi author Conde-San Román, Patricia author Rodriguez-Garcia, Mercedes author 2018 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. Immunity . 2018 Nov 20;49(5):819-828.e6. http://hdl.handle.net/20.500.12105/10393 30413362 10.1016/j.immuni.2018.09.008 1097-4180 Immunity Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.