新型白介素15 亚型蛋白在急性移植物抗宿主病中的作用及机制研究

During allogeneic hematopoietic stem cell transplantation (allogeneic HSCT), donor-derived allogeneic T cells can exert an important graft-versus-leukemia (GVL) effect. However, allogeneic T cells could also carry a significant risk for graft-versus-host disease (GVHD). A major goal of allogeneic HSCT, therefore, is to discover factors which can lessen GVHD lethality while maintaining GVL activity. Interleukin-15 (IL-15) is a pleiotropic proinflammatory cytokine. Studies have shown that donor hematopoietic-derived IL-15 is critical for promoting acute GVHD. Meanwhile, in the absence of donor-derived IL-15 expression, acute GVHD lethality is significantly decreased, yet GVL effects are maintained. Thus, donor-derived IL-15 could be pursued as a target for neutralization in GVHD prophylaxis and treatment. Recently, we have identified a novel isoform of IL-15 mRNA generated by splicing events of activated immune cells which could inhibit the effects of normal IL-15. We also found that this IL-15 isoform protein could obviously reduce the disease symptoms of experimental autoimmune encephalomyelitis (EAE) and inhibit the inflammation reaction. Different from the artificial synthetic IL-15 and IL-15 receptor antagonist, the negative immune regulation of this naturally occurring IL-15 isoform protein will be more safe and effective. The current project intends to determine the role and immune mechanism of this IL-15 isoform in preventing recipients from developing acute GVHD in murine allogeneic HSCT. Furthermore, we will address the role of this IL-15 isoform in dissecting harmful acute GVHD from the beneficial GVL effect. The data obtained from this aim may have significant implication in the optimization of allogeneic HSCT program.

异基因造血干细胞移植中异基因反应性T细胞发挥了重要的移植物抗白血病效应(GVL)但同时也会导致移植物抗宿主病(GVHD)。如何能够在有效抑制GVHD的同时兼顾维持GVL功能是提升异基因造血干细胞移植疗效的关键。IL-15是功能强大的多效促炎细胞因子，研究证明供体造血干细胞来源的IL-15显著促进GVHD病情，而清除该内源性IL-15在显著抑制GVHD的同时并不影响GVL效应，因此供体来源的IL-15是防治GVHD的理想靶点。本课题前期发现一种新型IL-15亚型蛋白，体外实验及小鼠脑脊髓炎实验证明该蛋白系免疫细胞在激活状态下天然形成的IL-15负向调节蛋白，能够显著减轻EAE小鼠病情，抑制体内炎症反应。与人工合成的 拮抗剂不同，其在体内的调节作用将更安全有效。本研究将明确该IL-15亚型对GVHD的抑制作用与机制，及其对GVL效应的影响，从而为优化异基因造血干细胞移植方案提供可靠的理论基础。

急性移植物抗宿主病（GVHD）是异基因造血干细胞移植后危及患者生命的主要并发症之一，如何能够在有效减轻急性GVHD病情的同时维持移植物抗白血病（GVL）效应是临床治疗中亟需解决的难题。白细胞介素15是功能强大的多效促炎细胞因子，其水平升高能够促进炎性细胞因子分泌，抑制T细胞激活后凋亡，促进CD8+记忆性T细胞存活。本课题组前期工作发现一种新型 IL-15 亚型蛋白，系免疫细胞在激活状态下经选择性剪切而形成，蛋白结构模拟及体外实验初步证明此亚型蛋白可能通过与受体的竞争性结合而抑制野生型 IL-15 的功能，发挥负向调节作用。基于此，本课题利用急性GVHD小鼠模型观察该IL-15亚型蛋白的输注在急性GVHD中的作用，并探寻其作用机制。课题组实验结果表明，IL-15亚型蛋白的输注能够显著减轻急性GVHD小鼠病情，延长其生存周期，同时并不影响GVL效应。其免疫调节作用的发挥可能是通过与IL-15竞争结合IL-15Rα，进而降低受体鼠体内炎性细胞因子表达水平，减轻供体T细胞异基因反应活性及增殖能力。本课题的实验结果为明确IL-15亚型蛋白在异基因造血干细胞移植中的临床应用前景提供了理论依据及实验基础。