IL-33／ST2信号途径在异基因造血干细胞移植后急性GVHD/GVL的调控作用及其机制

Using wild-type or ST2-/ - mice as bone marrow donor, the recipient mice were intraperitoneally injected of rIL-33 after allogeneic bone marrow transplantation (Allo-BMT) to prove that IL-33/ST2L signaling pathways is a negative regulator for acute GVHD (aGVHD) ; We also proposed the mechanism of IL-33/ST2L signaling pathways to induce aGVHD immune tolerance by Th2 cells /Treg cell responses and up-regulating the expression of CD103 + IDO + DC cells , CD11b + Gr-1int cells (MDSCs). Allogeneic bone marrow transplantation model was established in leukemic mice to explore the impact of IL-33 for GVL effect. The anti-leukemic activities of NK cells and macrophages were evaluated through co-cultures of IL-33 stimulated NK cells and macrophages with target leukemic cells. The study provides a theoretical basis for the clinical application of IL-33 to modulate IL-33/ST2 signaling pathways for the prophylaxis and treatment of GVHD while preserving GVL effects.

本研究通过野生型和ST2-/-小鼠作为供体异基因骨髓移植（Allo-BMT）后受鼠腹腔注射rIL-33证实 IL-33/ST2L信号途径对急性GVHD具有负性调节作用，提出了IL-33/ST2L信号途径通过诱导Th2细胞/Treg细胞应答和CD103+IDO+DC细胞、CD11b+Gr-1int细胞（MDSCs）表达发挥aGVHD免疫耐受的作用机理。建立白血病小鼠的异基因骨髓移植模型并探讨IL-33减轻aGVHD的同时对GVL效应的影响； 通过体外NK细胞/白血病细胞及巨噬细胞/白血病细胞共培养研究IL-33对GVL效应细胞功能影响。该研究为临床应用IL-33和调节IL-33/ST2信号途径来预防和治疗GVHD并且维持GVL效应提供理论依据。

我们构建 aGVHD 的小鼠模型，受鼠腹腔注射rIL-33或尾静脉注射抗ST2 mAb，观察各组小鼠的GVHD评分及生存期，通过体外实验，研究rIL-33对T淋巴细胞增殖及分化影响，及体外NK细胞/白血病细胞共培养研究IL-33对GVL效应细胞功能影响。结果表明，注射rIL-33可减轻小鼠aGVHD,而抗ST2 mAb加重小鼠GVHD。证实 IL-33/ST2L信号途径对急性GVHD具有负性调节作用，IL-33与其受体ST2L结合通过刺激Th2/Treg偏移及诱导MDSCs细胞扩增来诱导免疫耐受，IL-33可增强NK细胞杀伤功能。在GVHD患者，IL33及sST2水平与GVHD的严重程度有关，该研究为临床应用IL-33和调节IL-33/ST2信号途径来预防和治疗GVHD提供理论依据。