IL-27调控单倍型-脐血移植后免疫重建及移植物抗白血病效应研究

Haplo-cord SCT may improve the prognosis of haplo-identical donor SCT (haplo SCT), with decreased relapse incidence. However, its therapeutic mechanisms remain indeterminate. Our previous data showed a higher level of IL-27 in patients received haplo-cord SCT compared to those received haplo SCT. Moreover, a higher IL-27 level post-SCT was related to lower relapse incidence and longer survival. It has been reported that IL-27 may regulate the differentiation in hematopoietic stem cells, and the development and function of T cells, which promotes anti-tumor activity. We hypothesize that IL-27 may induce the immune reconstitution post haplo-cord SCT, and thereafter enhance the development and function of cytotoxic T cells, resulting in a more efficient graft-versus-host (GVL) effect. With the support of the grant, firstly we suppose to address the correlation between the IL-27 level and immune reconstitution as well as the level of residual disease by retrospective and prospective clinical studies, and furthermore to reveal the source of IL-27 post haplo-cord SCT. Secondly we plan to establish animal model of haplo-cord SCT involving IL-27p28 gene knockout mouse, in order to investigate the impact and the mechanisms of IL-27 on immune reconstitution and GVL effect post haplo-cord SCT. To determine the role of IL-27 may allow its further exploration of clinical intervention, and meanwhile may partially contribute to clarify the therapeutic mechanism of haplo-cord SCT.

单倍型-脐血移植（haplo-cord SCT）可提高移植预后，减少复发率，但机制未明。课题组前期发现haplo-cord SCT后IL-27水平显著高于单倍型供体移植患者，且IL-27高水平与低复发率、高生存率相关。文献报道IL-27可调节造血干细胞的分化与T细胞的发育和功能，提高抗肿瘤活性。因此我们推测IL-27通过促进移植后免疫重建和细胞毒T细胞功能，增强了移植后的移植物抗白血病（GVL）效应。本课题拟：①通过临床研究，明确移植后IL-27水平与haplo-cord SCT免疫重建及肿瘤负荷间的关系，并探讨移植后IL-27的来源；②利用IL-27敲基因小鼠构建haplo-cord SCT小鼠模型，阐明IL-27影响免疫重建和GVL效应的机制。明确IL-27在haplo-cord SCT中的作用可为其临床应用初步奠定基础，并为揭示haplo-cord SCT的疗效机制提供部分依据。

单倍型-脐血移植（haplo-cord SCT）可提高移植预后，移植后生存率优于传统的单倍型供体移植（haplo SCT），但机制尚不明确。课题组前期发现IL-27可能在haplo-cord SCT中发挥重要的免疫调节作用。本课题拟通过临床及基础研究，分析haplo-cord SCT疗效优势的潜在机制，及IL-27在其中的来源和作用，并探索IL-27对haplo-cord SCT后免疫重建的影响，尝试揭示IL-27调节haplo-cord SCT后免疫反应机制。在临床研究中，课题组分析了129例急性髓系白血病患者，发现Haplo-cord SCT患者的3年复发率（21.9±4.9% vs 32.0±7.2%，P = 0.146）和非复发死亡率（12.0±3.7% vs 25.4±6.4%，P=0.023）均优于haplo SCT患者，但复发率差异不显著。两组3年总生存率分别为76.8±4.8%和54.9±7.0%（P=0.001），无病生存率分别为69.2±5.2% vs 51.0±7.0%（P=0.010），haplo-cord SCT组均有显著优势。单细胞测序结果显示haplo-cord SCT后+3月脐血微嵌合仍然存在，并可能促进了移植后早期T细胞重建，从而降低了移植后复发与感染风险。在基础研究领域，课题组发现抗原递呈细胞，如巨噬细胞、树突状细胞等是移植后IL-27的主要来源。通过IL-27p28亚基基因敲除的小鼠移植模型研究发现，内源性IL-27缺失可上调供体T细胞的异体反应性，而外源性给予IL-27在移植物抗宿主病（GVHD）小鼠模型中加重GVHD反应。IL-27可能通过IL-27Rα介导来调节异体反应性T细胞（如产IFN-γ和产TNF-α的T细胞）和Treg细胞，从而发挥免疫调节作用。上述成果为解释和优化haplo-cord SCT的疗效、寻找新的干预靶点提供了部分理论和实验依据。