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Braza, Mounia S.; Leent, Mandy M. T. van; Lameijer, Marnix; Sanchez-Gaytan, Brenda L.; Arts, Rob J. W.; Perez-Medina, Carlos; Conde, Patricia; Garcia, Mercedes R.; Gonzalez-Perez, Maria; 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, Raphael; Fayad, Zahi A.; Netea, Mihai G.; Mulder, Willem J. M. and Ochando, Jordi (2018): Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance. In: Immunity, Vol. 49, No. 5: pp. 819-828

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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.

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