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. Calcagno & 13 others Florent 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

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)

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.

LanguageEnglish
Pages819-828.e6
Number of pages17
JournalImmunity
Volume49
Issue number5
DOIs
StatePublished - 20 Nov 2018

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Myeloid Cells
HDL Lipoproteins
Allografts
Inflammation
Transplants
Organ Transplantation
Macrophages
Regulatory T-Lymphocytes
TNF Receptor-Associated Factor 6
Cytokines
Therapeutics
Toll-Like Receptor 4
Macrophage Activation
Glycolysis
Immunosuppressive Agents
Innate Immunity
Epigenomics
Cellular Immunity
Immunotherapy
Immunosuppression

Keywords

  • CD40
  • immunotherapy
  • innate immune memory
  • mTOR
  • nanoimmunotherapy
  • TRAF6
  • trained immunity
  • transplantation

Cite this

Braza, M. S., van Leent, M. M. T., Lameijer, M., Sanchez-Gaytan, B. L., Arts, R. J. W., Pérez-Medina, C., ... Ochando, J. (2018). Inhibiting inflammation with Myeloid cell-specific nanobiologics promotes organ transplant acceptance. Immunity, 49(5), 819-828.e6. DOI: 10.1016/j.immuni.2018.09.008
Braza, Mounia S. ; van Leent, Mandy M.T. ; Lameijer, Marnix ; Sanchez-Gaytan, Brenda L. ; Arts, Rob J.W. ; Pérez-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, Raphaël ; Fayad, Zahi A. ; Netea, Mihai G. ; Mulder, Willem J.M. ; Ochando, Jordi. / Inhibiting inflammation with Myeloid cell-specific nanobiologics promotes organ transplant acceptance. In: Immunity. 2018 ; Vol. 49, No. 5. pp. 819-828.e6
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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.",
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Braza, MS, van Leent, MMT, Lameijer, M, Sanchez-Gaytan, BL, Arts, RJW, Pérez-Medina, C, Conde, P, Garcia, MR, Gonzalez-Perez, M, Brahmachary, M, Fay, F, Kluza, E, Kossatz, S, Dress, RJ, Salem, F, Rialdi, A, Reiner, T, Boros, P, Strijkers, GJ, Calcagno, CC, Ginhoux, F, Marazzi, I, Lutgens, E, Nicolaes, GAF, Weber, C, Swirski, FK, Nahrendorf, M, Fisher, EA, Duivenvoorden, R, Fayad, ZA, Netea, MG, Mulder, WJM & Ochando, J 2018, 'Inhibiting inflammation with Myeloid cell-specific nanobiologics promotes organ transplant acceptance' Immunity, vol. 49, no. 5, pp. 819-828.e6. DOI: 10.1016/j.immuni.2018.09.008

Inhibiting inflammation with Myeloid cell-specific nanobiologics promotes organ transplant acceptance. / Braza, Mounia S.; van Leent, Mandy M.T.; Lameijer, Marnix; Sanchez-Gaytan, Brenda L.; Arts, Rob J.W.; Pérez-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, Raphaël; Fayad, Zahi A.; Netea, Mihai G.; Mulder, Willem J.M.; Ochando, Jordi.

In: Immunity, Vol. 49, No. 5, 20.11.2018, p. 819-828.e6.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Inhibiting inflammation with Myeloid cell-specific nanobiologics promotes organ transplant acceptance

AU - Braza,Mounia S.

AU - van Leent,Mandy M.T.

AU - Lameijer,Marnix

AU - Sanchez-Gaytan,Brenda L.

AU - Arts,Rob J.W.

AU - Pérez-Medina,Carlos

AU - Conde,Patricia

AU - Garcia,Mercedes R.

AU - Gonzalez-Perez,Maria

AU - Brahmachary,Manisha

AU - Fay,Francois

AU - Kluza,Ewelina

AU - Kossatz,Susanne

AU - Dress,Regine J.

AU - Salem,Fadi

AU - Rialdi,Alexander

AU - Reiner,Thomas

AU - Boros,Peter

AU - Strijkers,Gustav J.

AU - Calcagno,Claudia C.

AU - Ginhoux,Florent

AU - Marazzi,Ivan

AU - Lutgens,Esther

AU - Nicolaes,Gerry A.F.

AU - Weber,Christian

AU - Swirski,Filip K.

AU - Nahrendorf,Matthias

AU - Fisher,Edward A.

AU - Duivenvoorden,Raphaël

AU - Fayad,Zahi A.

AU - Netea,Mihai G.

AU - Mulder,Willem J.M.

AU - Ochando,Jordi

PY - 2018/11/20

Y1 - 2018/11/20

N2 - 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.

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KW - immunotherapy

KW - innate immune memory

KW - mTOR

KW - nanoimmunotherapy

KW - TRAF6

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KW - transplantation

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Braza MS, van Leent MMT, Lameijer M, Sanchez-Gaytan BL, Arts RJW, Pérez-Medina C et al. Inhibiting inflammation with Myeloid cell-specific nanobiologics promotes organ transplant acceptance. Immunity. 2018 Nov 20;49(5):819-828.e6. Available from, DOI: 10.1016/j.immuni.2018.09.008