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.
Original language | English |
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Pages (from-to) | 819-828.e6 |
Number of pages | 17 |
Journal | Immunity |
Volume | 49 |
Issue number | 5 |
DOIs | |
Publication status | Published - 20 Nov 2018 |
Keywords
- CD40
- immunotherapy
- innate immune memory
- mTOR
- nanoimmunotherapy
- TRAF6
- trained immunity
- transplantation
- HMGB1 Protein/genetics
- Vimentin/genetics
- Immune Tolerance
- Organ Transplantation
- Macrophages/immunology
- Immunity, Innate
- Inflammation/immunology
- Myeloid Cells/immunology
- Immunosuppression
- Allografts
- Animals
- Biomarkers
- Immunologic Memory
- Graft Survival/immunology
- Mice
- TOR Serine-Threonine Kinases/metabolism
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Nanotechnology-Based Immunotherapy that Promotes Organ Transplant Acceptance
7/11/18
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