Heme oxygenase-1 as a therapeutic target in anti-HLA antibody-triggered transplant vasculopathy

血红素加氧酶 1 作为抗 HLA 抗体触发的移植血管病的治疗靶点

• 批准号: 265437184
• 负责人: Professor Dr. Stephan Immenschuh
• 金额: --
• 依托单位: Institut für Transfusionsmedizin und Transplantat Engineering
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/265437184?language=en
• 关键词: Heme; oxygenase; therapeutic; target; anti

Transplant vasculopathy (TV), a hallmark of chronic transplant rejection, is a major limiting factor for graft survival after heart and kidney transplantation, in which current therapeutic regimens are largely ineffective. TV is characterized by rapid narrowing of allograft vessels with progressive ischemia and graft failure. Ligation of de novo anti-HLA antibodies with the vascular endothelium plays a key role in the pathogenesis of this disorder. Similar to atherosclerosis, TV is characterized by increased cell proliferation and chronic inflammation of arteries. As inflammation is closely associated with oxidative stress, regulation of the vascular redox homeostasis appears to be critical in the pathogenesis of TV. The antioxidant inducible enzyme heme oxygenase (HO)-1 has major anti-inflammatory effects mediated by metabolic degradation of proinflammatory free heme as well as production of carbon monoxide (CO) and biliverdin. In addition, overexpression of HO-1 has been shown to be beneficial in various experimental models of inflammation and transplantation. The goal of this proposal is to gain a comprehensive understanding on the role of HO-1 in vascular cells for the pathogenesis and therapy of anti-HLA antibody-triggered TV. In particular, the therapeutic potential of pre-emptive pharmacological targeting to HO-1 in this disorder will be investigated.

移植物血管病变（TV）是慢性移植排斥反应的标志，是心脏和肾脏移植后移植物存活的主要限制因素，其中目前的治疗方案在很大程度上无效。TV的特征是移植血管迅速狭窄，伴有进行性缺血和移植物衰竭。新生抗HLA抗体与血管内皮的连接在这种疾病的发病机制中起着关键作用。与动脉粥样硬化相似，TV的特征在于增加的细胞增殖和动脉的慢性炎症。由于炎症与氧化应激密切相关，因此血管氧化还原稳态的调节似乎在TV的发病机制中至关重要。抗氧化诱导酶血红素加氧酶（HO）-1具有主要的抗炎作用，其通过促炎游离血红素的代谢降解以及一氧化碳（CO）和胆绿素的产生介导。此外，HO-1的过表达已被证明在各种炎症和移植的实验模型中是有益的。本研究的目的是全面了解HO-1在血管细胞中的作用，为抗HLA抗体触发的TV的发病机制和治疗提供理论依据。特别是，在这种疾病的先发制人的药理学靶向HO-1的治疗潜力将进行研究。

项目成果

Labile Heme Aggravates Renal Inflammation and Complement Activation After Ischemia Reperfusion Injury

• DOI: 10.3389/fimmu.2019.02975
• 发表时间: 2019-12
• 期刊: Frontiers in Immunology
• 影响因子: 7.3
• 作者: Li Wang;Vijith Vijayan;Mi-Sun Jang;A. Thorenz;Robert Greite;S. Rong;Rongjun Chen;N. Shushakova;I. Tudorache;K. Derlin;P. Pradhan;K. Madyaningrana;N. Madrahimov;J. Bräsen;R. Lichtinghagen;C. van Kooten;M. Huber-Lang;H. Haller;S. Immenschuh;F. Gueler

HLA class II antibodies induce necrotic cell death in human endothelial cells via a lysosomal membrane permeabilization-mediated pathway

• DOI: 10.1038/s41419-019-1319-5
• 发表时间: 2019-03-08
• 期刊: CELL DEATH & DISEASE
• 影响因子: 9
• 作者: Aljabri, Abid;Vijayan, Vijith;Immenschuh, Stephan
• 通讯作者: Immenschuh, Stephan

TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages.

• DOI: 10.1016/j.freeradbiomed.2019.04.024
• 发表时间: 2019-06
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Kritika Sudan;Vijith Vijayan;K. Madyaningrana;F. Gueler;K. Igarashi;R. Foresti;R. Motterlini;S. Immens

Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis

• DOI: 10.1016/j.redox.2019.101147
• 发表时间: 2019-04-01
• 期刊: REDOX BIOLOGY
• 影响因子: 11.4
• 作者: Vijayan, Vijith;Pradhan, Pooja;Immenschuh, Stephan
• 通讯作者: Immenschuh, Stephan

Ischemia Reperfusion Injury Triggers CXCL13 Release and B-Cell Recruitment After Allogenic Kidney Transplantation

• DOI: 10.3389/fimmu.2020.01204
• 发表时间: 2020-08-06
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Kreimann, Kirill;Jang, Mi-Sun;Gueler, Faikah
• 通讯作者: Gueler, Faikah