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.
| Language | English |
|---|---|
| Pages | 819-828.e6 |
| Number of pages | 17 |
| Journal | Immunity |
| Volume | 49 |
| Issue number | 5 |
| DOIs | |
| State | Published - 20 Nov 2018 |
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Keywords
- CD40
- immunotherapy
- innate immune memory
- mTOR
- nanoimmunotherapy
- TRAF6
- trained immunity
- transplantation
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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 journal › Article › Academic › peer-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.
AB - 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.
KW - CD40
KW - immunotherapy
KW - innate immune memory
KW - mTOR
KW - nanoimmunotherapy
KW - TRAF6
KW - trained immunity
KW - transplantation
UR - http://www.scopus.com/inward/record.url?scp=85056688855&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2018.09.008
DO - 10.1016/j.immuni.2018.09.008
M3 - Article
VL - 49
SP - 819-828.e6
JO - Immunity
T2 - Immunity
JF - Immunity
SN - 1097-4180
IS - 5
ER -