Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.
Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.
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DOI：
10.1016/j.immuni.2018.09.008
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发表时间：
2018-11-20
期刊：
影响因子：
32.4
通讯作者：
Ochando J
中科院分区：
文献类型：
--
作者：
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
诱导移植物接受而不慢性免疫抑制仍然是器官移植中难以实现的目标。使用实验性移植小鼠模型，我们证明了通过dectin-1和toll样受体4（TLR 4）的局部巨噬细胞活化在同种异体移植排斥反应期间驱动训练的免疫相关细胞因子的产生。我们进行了纳米免疫学研究，发现短期mTOR特异性高密度脂蛋白（HDL）纳米生物学治疗（mTORi-HDL）避免了巨噬细胞有氧糖酵解和炎症细胞因子产生背后的表观遗传修饰。由此产生的调节性巨噬细胞阻止同种异体反应性CD 8 + T细胞介导的免疫，并促进致耐受性CD 4+调节性T细胞（Treg）扩增。为了增强治疗功效，我们用抑制共刺激的CD 40-TRAF 6特异性纳米生物制剂（TRAF 6 i-HDL）补充mTORi-HDL治疗。这种协同纳米免疫疗法导致了无限期的同种异体移植物存活。总之，我们表明基于HDL的纳米免疫疗法可以用于控制体内巨噬细胞功能。我们的策略，专注于预防炎症性先天免疫反应，为开发促进免疫耐受的靶向治疗提供了一个框架。器官移植中一个尚未解决的问题是在缺乏长期免疫抑制治疗的情况下建立移植物接受性。Braza等人揭示了实验性器官移植模型中髓样细胞活化的重要分子机制，并开发了一种靶向造血器官和同种异体移植物中髓样细胞的联合纳米免疫疗法。短期纳米生物免疫疗法可预防炎症并诱导无限期同种异体移植物存活。
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. An unresolved problem in organ transplantation is to establish graft acceptance in the absence 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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单核细胞的先天同种异体及其在移植排斥中的作用。
DOI：
10.1111/ajt.14436
发表时间：
2018-03
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Lakkis FG;Li XC
通讯作者：
Li XC
DOI：
10.1111/ajt.14645
发表时间：
2018-05
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Braza MS;Conde P;Garcia M;Cortegano I;Brahmachary M;Pothula V;Fay F;Boros P;Werner SA;Ginhoux F;Mulder WJM;Ochando J
通讯作者：
Ochando J
影响因子：
20.3
作者：
Hackstein, H;Taner, T;Thomson, AW
通讯作者：
Thomson, AW
影响因子：
15.9
作者：
Oberbarnscheidt, Martin H.;Zeng, Qiang;Lakkis, Fadi G.
通讯作者：
Lakkis, Fadi G.
影响因子：
6.2
作者：
HANCOCK, WW;THOMSON, NM;ATKINS, RC
通讯作者：
ATKINS, RC