Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance

Abstract

SUMMARY 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 cell (Treg) 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 nanoimunnotherapy 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.

Defining trained immunity and its role in health and disease

“…Trained immunity could, in part, explain the epidemiological link between infections and atherosclerotic cardiovascular disease 143,144 . In addition to microbial products, endogenous triggers of innate immunity, including oxidized low-density lipoprotein particles, lipoprotein (a), vimentin and highmobility group box 1 (HMGB1), can induce trained immunity [145][146][147] .…”

“…Another clinical scenario in which sterile endogenous stimuli could trigger trained immunity in monocyte-derived cells is organ transplantation 146 . Braza et al 146 recently showed in a mouse heart transplantation model that donor allografts upregulate vimentin and HMGB1, which induced local training of graft-infiltrating monocyte-derived cells. Short-term treatment with a high-density lipoprotein nanobiologic that specifically inhibited mTOR in myeloid cells was able to prevent aerobic glycolysis and epigenetic modifications underlying trained immunity.…”

“…therefore, suppressing ongoing trained immunity or preventing its induction will be a relevant treatment modality for numerous diseases associated with a chronic inflammatory state. in addition, Ochando and colleagues 146 recently implicated trained immunity in organ rejection. using a trained immunity-inhibiting and mechanistic target of rapamycin (mtOr)-specific nanotherapeutic, they showed that a short treatment regimen resulted in prolonged allograft survival without the need for long-term immunosuppression in a mouse heart transplantation model.…”

Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

“…This could be achieved, for example, by enhancing negative regulation of TLR signaling and silent clearance of apoptotic cells (33,(355)(356)(357)(358)(359), as well as by augmenting IL-10 receptor signaling (360)(361)(362). To note, thanks to their high phagocytic capacity, targeting intestinal Mfs could be facilitated by "delivery systems" such as nanomaterials and biomaterials (363), as has been shown in mouse model of organ transplantation (364).…”

Nanotherapy that prevents trained immunity and promotes tolerance

“…Using a short-term regimen, long-term acceptance of the transplanted organ was achieved in the absence of serious side effects. 1 The nanomimmunotherapy consisted of high-density lipoprotein (HDL) nanobiologics, which they previously reported to specifically target myeloid cells in vivo. 2 In the current study, the authors demonstrate that HDL-nanobiologics target myeloid cells in the heart allograft and myeloid cell precursors in the bone marrow of transplant recipient mice.…”