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

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.

SUBMITTER: Braza MS

PROVIDER: S-EPMC6251711 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Braza Mounia S MS van Leent Mandy M T MMT Lameijer Marnix M Sanchez-Gaytan Brenda L BL Arts Rob J W RJW Pérez-Medina Carlos C Conde Patricia P Garcia Mercedes R MR Gonzalez-Perez Maria M Brahmachary Manisha M Fay Francois F Kluza Ewelina E Kossatz Susanne S Dress Regine J RJ Salem Fadi F Rialdi Alexander A Reiner Thomas T Boros Peter P Strijkers Gustav J GJ Calcagno Claudia C CC Ginhoux Florent F Marazzi Ivan I Lutgens Esther E Nicolaes Gerry A F GAF Weber Christian C Swirski Filip K FK Nahrendorf Matthias M Fisher Edward A EA Duivenvoorden Raphaël R Fayad Zahi A ZA Netea Mihai G MG Mulder Willem J M WJM Ochando Jordi J

Immunity 20181106 5

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 ...[more]

PMID: 30413362

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Project description:ImportanceUnder the current Centers for Medicare & Medicaid Services guidelines, there is incentivization to optimize posttransplant outcomes regardless of mortality among patients on the waitlist and transplant rates; few data exist with regard to transplant center acceptance practices and survival to heart transplant.ObjectivesTo evaluate the extent of variability in organ acceptance practices in the US and whether this center-level behavior is associated with heart transplant candidate survival.Design, setting, and participantsIn this retrospective cohort study, the US National Transplant Registry was queried for all match runs of adult candidates listed for isolated heart transplant between May 1, 2007, and March 31, 2017. Data analysis was conducted from October 30, 2018, to May 1, 2019. The final cohort included 93 transplant centers, 19 703 donors, and 9628 candidates.Main outcomes and measuresCenter acceptance rates for heart allografts offered to the highest-priority candidates, association between center acceptance rate and mortality among patients on the waitlist, and posttransplant outcomes between candidates who accepted their first-rank offers vs those who accepted previously declined offers.ResultsAmong 19 703 unique organ offers, 6302 hearts (32.0%) were accepted for first-rank candidates. After adjustment for donor, candidate, and geographic covariates, transplant centers varied in acceptance rates (12.3%-61.5%) of offers made to first-rank candidates. Higher acceptance rates were associated with lower cumulative incidence of 1-year mortality among patients on the waitlist. For every 10% increase in adjusted center acceptance rate, the risk of mortality decreased by 27% (subdistribution hazard ratio, 0.73; 95% CI, 0.67-0.80). No statistically significant difference was observed in 5-year adjusted posttransplant patient survival (adjusted hazard ratio, 1.02; 95% CI, 0.94-1.11) and graft failure (subdistribution hazard ratio; 0.95; 95% CI, 0.83-1.09) between hearts accepted at the first-rank compared with lower-rank positions.Conclusions and relevanceVariability in heart allograft acceptance rates appears to exist among transplant centers, with candidates listed at lower acceptance rate centers being more likely to experience mortality while on the waitlist. Comparable posttransplant survival suggests that allografts that were declined as a first offer perform as well as those that were accepted at their first offer. These findings suggest that organ acceptance rate or time to transplant from being added to the waitlist may be an additional measure of heart transplant program performance.

Dataset Information

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

Publications

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

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