Therapeutic approach to allergic disorders by focusing on Caspase-1/IL18.

以 Caspase-1/IL18 为重点的过敏性疾病治疗方法。

• 批准号: 11557039
• 负责人: NAKANISHI Kenji
• 金额: $ 8.26万
• 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 (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557039/
• 关键词: IL-18; Cspase-1; IgE; CD4+^T cell; KCASP1Tg; KIL-18Tg; Innate type allergy; Caspase-1; アトピー性皮膚炎(AD); 高IgE血症; Caspase-1阻害剤; アトピー様症状; Caspase-1遺伝子トランスジェニックマウス

IL-18 was discovered as a factor that enhances IFN-y production from Thl cells in the presence of anti-CD3 and IL-12.Like IL-lp, IL-18 is synthesized as a precursor protein that requires cleavage with caspase-1 to become active. As biological action of IL-18 had been investigated under the presence of IL-12, IL-18 had been rabelled as an IFN-Y inducing factor. However, we demonstrated that IL-18 causes high-level IgE production when administered to normal mice by causing CD4* T cells to produce IL-4 and to express CD40L.Atopic dermatitis (AD) is pruritic skin disease induced by the products of basophils and mast cells. As IL-18 directly stimulates these cells to produce IL-4, IL-13 and histamine, we investigated whether IL-18 can induce atopic response without being encountered with allergen or IgE induction. For this purpose, we established KCASPlTg or KIL-18Tg which over-express IL-18 or caspase-1 gene in their keratinocytes, respectively.Both types of transgenic mice produce large a … More mounts of IL-18, IgE and histamine and spontaneously develop chronic dermatitis accumulated with mast cells under SPF condition. Deletion of stat6 gene in KCASPlTg completely abrogated IgE production without eliminating their cutaneous changes, suggesting that IL-18 but not IgE induces these pathological changes. We next established KCASPlTg lacking IL-18 and found that this depletion almost completely abrogated cutaneous alternation. On the other hand, KJL-18Tg took much longer time to display these atopic phenotypes than KCASPlTg. Moreover, depletion of IL-1 gene in KCASPlTg delayed this onset. Therefore, atopic inflammation might be initiated by over-release of IL-18 and accelerated by IL-1.Our data may allow us to propose to classify atopy to allergen/ IgE-dependent atopy (acquired type allergy) and IL-18-dependent but IgE-independent atopy (innate type allergy). Furthermore, our data suggest that therapeutic approach focusing on Caspase-l/IL-18 as a target molecule will provide us a new insight into the establishment of the treatment for allergic disorder. Less

发现IL-18是在抗-CD 3和IL-12存在下增强Thl细胞产生IFN-γ的因子。与IL-1 β一样，IL-18作为前体蛋白合成，其需要用半胱天冬酶-1切割以变得有活性。随着IL-18在IL-12存在下的生物学作用的研究，IL-18被认为是IFN-γ诱导因子。然而，我们发现IL-18通过诱导正常小鼠的CD 4 * T细胞产生IL-4和表达CD 40 L，从而引起高水平的IgE产生。特应性皮炎（AD）是由嗜碱性粒细胞和肥大细胞的产物诱导的皮炎性皮肤病。由于IL-18直接刺激这些细胞产生IL-4、IL-13和组胺，我们研究了IL-18是否可以诱导特应性反应而不遇到过敏原或IgE诱导。为此，我们分别建立了过表达IL-18或caspase-1基因的KCASPlTg或KIL-18 Tg转基因小鼠，这两种转基因小鼠均产生了大量的白细胞介素-18（IL-18）和白细胞介素-18（caspase-1）。 ...更多信息 大量的IL-18、IgE和组胺，并在SPF条件下自发地发展成肥大细胞积聚的慢性皮炎。KCASPlTg中stat 6基因的缺失完全消除了IgE的产生，而没有消除它们的皮肤变化，这表明IL-18而不是IgE诱导这些病理变化。我们接下来建立了缺乏IL-18的KCASPlTg，并发现这种消耗几乎完全消除了皮肤变化。另一方面，KJL-18 Tg比KCASPlTg花费长得多的时间来显示这些特应性表型。此外，KCASPlTg中IL-1基因的缺失延迟了这种发作。因此，特应性炎症可能是由IL-18的过度释放引发的，而IL-1则加速了炎症的发生。我们的数据可能使我们建议将特应性分为过敏原/IgE依赖性特应性（获得性变态反应）和IL-18依赖但IgE非依赖性特应性（先天性变态反应）。此外，我们的数据表明，以Caspase-1/IL-18为靶分子的治疗方法将为我们建立过敏性疾病的治疗提供新的见解。少

项目成果

Nakanishi, K., et al.: "Cytokine Therapeuticx in Infectious Diseases (Holland, S.M.eds.)"Lippincott Williams & Wilkins. 26 (2001)

Nakanishi, K. 等人：“传染病中的细胞因子治疗（Holland，S.M.eds.）”Lippincott Williams

Chang,J.T., et al.: "The costimulatory effect of IL-18 on the induction of antigen-specific IFN-γ production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor β2 submit."Eur.J.Immunol.. 30. 1113-1119 (2000)

Chang, J.T. 等人：“IL-18 对静息 T 细胞诱导抗原特异性 IFN-γ 产生的共刺激作用是 IL-12 依赖性的，并且由 IL-12 受体 β2 的上调介导。提交。“Eur.J.Immunol.. 30. 1113-1119 (2000)

善本知広 他: "Annual Review 免疫1999"中外医学者. 13 (1999)

Tomohiro Yoshimoto 等人：“免疫学年度评论 1999”Chugai Igakusha 13 (1999)。

Hoshino, K., et al.: "The absence of Interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function"J.Exp.Med.. 190. 1541-1548 (1999)

Hoshino, K., 等人：“白细胞介素 1 受体相关 T1/ST2 的缺失不会影响 2 型辅助 T 细胞的发育及其效应功能”J.Exp.Med.. 190. 1541-1548 (1999)

Tsutsui,H.,et al.: "Caspase-1-independetnt, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice"Immunity. 11. 359-367 (1999)

Tsutsui, H., et al.：“不依赖 Caspase-1、Fas/Fas 配体介导的巨噬细胞分泌 IL-18 导致小鼠急性肝损伤”免疫。