Moreau A, Hill M, Thébault P, Deschamps J Y, Chiffoleau E, Chauveau C, Moullier P, Anegon I, Alliot-Licht B, Cuturi M C
INSERM U643, CHU Hotel-Dieu, Nantes, France.
FASEB J. 2009 Sep;23(9):3070-7. doi: 10.1096/fj.08-128173. Epub 2009 May 6.
Clinical translation of dendritic cell (DC)-based cell therapy requires preclinical studies in nonhuman primates (NHPs). The aim of this work was to establish the in vitro conditions for generation of NHP tolerogenic DCs (Tol-DCs), as well as to analyze the molecular mechanisms by which these cells could control an immune response. Two populations of NHP bone marrow-derived DCs (BMDCs) were obtained: adherent and nonadherent. Although both populations displayed a quite similar phenotype, they were very different functionally. We characterized the adherent BMDCs as Tol-DCs that were poor stimulators of T cells and actively inhibited T-cell proliferation, whereas the nonadherent population displayed immunogenic properties in vitro. Interestingly, the anti-inflammatory and immunosuppressive enzyme heme oxygenase-1 (HO-1) was up-regulated in Tol-DCs, compared to the immunogenic BMDCs. We demonstrated that HO-1 mediates the immunosuppressive properties of Tol-DCs in vitro (in NHPs and rats) and that HO-1 is involved in the in vivo tolerogenic effect of Tol-DCs in a rat model of allotransplantation. In conclusion, here we characterized the in vitro generation of NHP Tol-DCs. Furthermore, we showed for the first time that HO-1 plays a role in the active inhibition of T-cell responses by rat and NHP Tol-DCs.
基于树突状细胞（DC）的细胞疗法的临床转化需要在非人类灵长类动物（NHP）中进行临床前研究。这项工作的目的是建立体外生成NHP耐受性DC（Tol-DC）的条件，并分析这些细胞控制免疫反应的分子机制。获得了两类NHP骨髓来源的DC（BMDC）：贴壁型和非贴壁型。尽管这两类细胞表现出非常相似的表型，但它们在功能上却有很大差异。我们将贴壁BMDC鉴定为Tol-DC，它们是T细胞的弱刺激剂，并能积极抑制T细胞增殖，而非贴壁型细胞在体外表现出免疫原性。有趣的是，与免疫原性BMDC相比，抗炎和免疫抑制酶血红素加氧酶-1（HO-1）在Tol-DC中上调。我们证明HO-1在体外（在NHP和大鼠中）介导Tol-DC的免疫抑制特性，并且HO-1参与了同种异体移植大鼠模型中Tol-DC的体内耐受性效应。总之，我们在此描述了NHP Tol-DC的体外生成特征。此外，我们首次表明HO-1在大鼠和NHP Tol-DC对T细胞反应的主动抑制中发挥作用。
