Braza, Mounia Svan Leent, Mandy M TLameijer, MarnixSanchez-Gaytan, Brenda LArts, Rob J WPerez-Medina, CarlosGonzalez-Perez, MariaBrahmachary, ManishaFay, FrancoisKluza, EwelinaKossatz, SusanneDress, Regine JSalem, FadiRialdi, AlexanderReiner, ThomasBoros, PeterStrijkers, Gustav JCalcagno, ClaudiaGinhoux, FlorentMarazzi, IvanLutgens, EstherNicolaes, Gerry A FWeber, ChristianSwirski, Filip KNahrendorf, MatthiasFisher, Edward ADuivenvoorden, RaphaëlFayad, Zahi ANetea, Mihai GMulder, Willem J MOchando, JordiConde-San Román, PatriciaRodriguez-Garcia, Mercedes2020-06-152020-06-152018Immunity . 2018 Nov 20;49(5):819-828.e6.http://hdl.handle.net/20.500.12105/10393Inducing 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.engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/ImmunosuppressionOrgan TransplantationAllograftsAnimalsBiomarkersGraft SurvivalHMGB1 ProteinImmune ToleranceImmunity, InnateImmunologic MemoryInflammationMacrophagesMiceMyeloid CellsTOR Serine-Threonine KinasesVimentinAttribution-NonCommercial-NoDerivatives 4.0 Internacional30413362495819-828.e610.1016/j.immuni.2018.09.0081097-4180Immunityopen access