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Pathological roles of interleukin-18 in graft-versus-host disease and rejection of grafts

IL-18 在移植物抗宿主病和移植物排斥中的病理作用

基本信息

批准号：
11670331
负责人：
TSUTSUI Hiroko
金额：
$ 0.77万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670331/
关键词：
acute GVHD IL-1 IL-18 Fas Fas ligand caspase-1 IFN-γ tissue injuries bone marrow transplantation 移植拒絶反応 GVHD interleukin 18 interleukin 12 ノックアウトマウス

项目摘要

Bone marrow transplantation is an effective therapy for hematopoietic malignancy, such as leukemia, and immunodeficient diseases. However, immunological reactions based on the difference of major histocompatibility complex occasionally cause various pathological changes in recipients. Acute graft-versus-host disease (aGVHD), fatal side effects of bone marrow transplantation, has been shown to be accompanied with elevation of serum levels of interleukin (IL) -18. IL-18 is a proinflammatory cytokine and is produced as biologically inactive precursor. After appropriate stimulation, precursor IL-18 is cleaved into mature IL-18 by caspase-1 or caspase-1-like enzyme, leading to release of mature IL-18. Here, we investigated the mechanism underlying the accumulation of IL-18 in aGVHD in mice. Lethally irradiated recipients transplanted with H-2 disparate donor splenocytes confessed aGVHD and contained markedly elevated serum levels of IL-18. While recipients transplanted with gld/gld spleen cells, that lack functional Fas ligand (FasL), contained only normal ranges of IL-18, indicating FasL-mediated IL-18 release in aGVHD.The wild type hosts engrafted with caspase-1-deficient cells revealed marked increases of IL-18 level similar to those engrafted with wild type cells, while caspase-1-deficient recipients engrafted with wild type cells showed only slight elevation of serum IL-18, indicating that IL-18 elevation is derived from host cells in a caspase-1-dependent manner. These results suggested FasL-mediated caspase-1-dependent IL-18 secretion in aGVHD in mice.

骨髓移植是一种有效的治疗造血恶性肿瘤，如白血病和免疫缺陷疾病。然而，基于主要组织相容性复合体差异的免疫反应偶尔会引起受体的各种病理改变。急性移植物抗宿主病（aGVHD）是骨髓移植的致命副作用，已被证明伴随着血清白细胞介素(IL) -18水平的升高。IL-18是一种促炎细胞因子，是作为生物无活性前体产生的。经过适当的刺激，前体IL-18被caspase-1或caspase-1样酶裂解成成熟IL-18，导致成熟IL-18释放。在这里，我们研究了IL-18在小鼠aGVHD中积累的机制。用H-2异种供体脾细胞进行致命照射的受者承认aGVHD，血清IL-18水平显著升高。而移植了gld/gld脾细胞的受体，缺乏功能性Fas配体（FasL），仅含有正常范围的IL-18，表明FasL介导的IL-18在aGVHD中释放。转染caspase-1缺陷细胞的野生型宿主IL-18水平明显升高，与转染野生型宿主相似，而转染caspase-1缺陷细胞的野生型宿主血清IL-18水平仅轻微升高，说明IL-18的升高是以caspase-1依赖性的方式来源于宿主细胞。这些结果提示fasl介导的caspase-1依赖性IL-18在aGVHD小鼠中的分泌。