应用芳香羟受体激动剂FICZ预防小鼠急性移植物抗宿主病的机制研究

Acute graft-versus-host disease(aGVHD) is one of the major complications after hematopoietic stem cell transplantation (HSCT). It has been indicated tha mucosal lesions in gastrointestinal tract(GI) by pretreatment before HSCT plays crucial role in the pathogenesis of aGVHD. Unfortunately, efficacy of the existing methods of GVHD prophylaxis was unsatisfactory. The applicant has found that administration of FICZ, an agonist of aryl hydrocarbon receptor, effectively prevented the occurrence of murine aGVHD and significantly alleviated the GI tract lesions. However, the underlying mechanism is not clear. The applicant hypotheses that the effect of FICZ on aGVHD via direct activation of AhR receptor leads to the expansion of IL-22+RORvt+ILC in the intestine in hosts, resulting in the recovery of mucosal lesions. Therefore, we will further investigate the relationship among FICZ, AhR, IL-22+RORvt+ILC cells and aGVHD and uncover its possible mechanism based on animal models, using AhR(d) and RORvt(gfp) transgeneic mice, and in vitro ILC culture system. Our study will provide a novel strategy for the prevention and treatment of aGVHD. To date, our study has not been reported by any research group.

急性移植物抗宿主病（aGVHD)是造血干细胞移植术（HSCT）后最严重的并发症之一。其中，移植前的预处理引起的胃肠道粘膜损伤在其发病中占有举足轻重的地位。然而，目前临床尚缺乏满意的预防方法。申请人的前期研究发现，AhR受体激动剂FICZ有效的预防了半相合移植小鼠aGVHD的发生，明显减轻了其胃肠道损伤，但具体机制不明确。我们推测FICZ可能通过激活AhR受体，继而体内扩增小鼠肠道IL-22+RORvt+ILC细胞，促进预处理引起的肠道粘膜的损伤修复，从而达到预防aGVHD的作用。我们拟采用AhR(d)和RORvt(gfp)转基因小鼠，应用aGVHD模型和ILC细胞的体外培养体系，从动物和细胞水平深入探讨“FICZ-AhR-IL22+RORvt+ILC细胞-aGVHD”的内在联系，研究其可能机制，为临床aGVHD的预防和治疗提供新的方向。本研究方案目前国内外均未见报道。

急性移植物抗宿主病（aGVHD)是造血干细胞移植术（HSCT）后最严重的并发症之一。其中，移植前的预处理引起的胃肠道粘膜损伤在其发病中占有举足轻重的地位。然而，目前临床尚缺乏满意的预防方法。申请人的前期研究发现，AhR受体激动剂FICZ有效的预防了半相合移植小鼠aGVHD的发生，明显减轻了其胃肠道损伤，但具体机制不明确。主要研究内容：应用aGVHD模型和ILC细胞的体外培养体系，从动物和细胞水平深入探讨“FICZ-AhR-IL22+RORvt+ILC细胞-aGVHD”的内在联系，研究其可能机制。重要结果：1、在[C57BL/6(H-2b)→[C57BL/6 x CBA/Ca(H-2bxk)]F1]小鼠骨髓移植模型中，供者来源的CD4+-和CD8+T细胞均能诱导致死性aGVHD的发生；2、供者来源的CD4+-和CD8+T细胞在aGVHD小鼠体内发生了增殖、分化，并攻击受者靶器官，导致多器官损伤；3、FICZ可抑制肠道aGVHD的发生，主要通过诱导产生IL-22+RORvt+ILC细胞发挥作用。本研究结果将为靶向RORγt+ILC 细胞治疗临床 aGVHD提供实验依据。

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