期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 18, 期 5, 页码 1096-1109出版社
WILEY
DOI: 10.1111/ajt.14544
关键词
alloantibody; animal models: murine; basic (laboratory) research; science; cellular biology; immunosuppressant - mechanistic target of rapamycin (mTOR); immunosuppression; immune modulation; macrophage; monocyte biology; organ transplantation in general; translational research; science; vasculopathy
资金
- Ruth L. Kirschstein National Research Service Award [T32HL69766, T32CA009120]
- National Intitutes of Health [AI042819]
- Pfizer Arts grants
Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1(-/-) recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR. Mechanistic target of rapamycin inhibition suppresses ezrin/radixin/moesin phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I antibody, and prevents macrophage infiltration into cardiac allografts. See the supplemental videos at .
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据