Inhibiting inflammation with Myeloid cell-specific nanobiologics promotes organ transplant acceptance

Mounia S. Braza, Mandy M.T. van Leent, Marnix Lameijer, Brenda L. Sanchez-Gaytan, Rob J.W. Arts, Carlos Pérez-Medina, Patricia Conde, Mercedes R. Garcia, Maria Gonzalez-Perez, Manisha Brahmachary, Francois Fay, Ewelina Kluza, Susanne Kossatz, Regine J. Dress, Fadi Salem, Alexander Rialdi, Thomas Reiner, Peter Boros, Gustav J. Strijkers, Claudia C. CalcagnoFlorent Ginhoux, Ivan Marazzi, Esther Lutgens, Gerry A.F. Nicolaes, Christian Weber, Filip K. Swirski, Matthias Nahrendorf, Edward A. Fisher, Raphaël Duivenvoorden, Zahi A. Fayad, Mihai G. Netea, Willem J.M. Mulder, Jordi Ochando

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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 languageEnglish
Pages (from-to)819-828.e6
Number of pages17
JournalImmunity
Volume49
Issue number5
DOIs
Publication statusPublished - 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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