Alpha-1 antitrypsin suppresses macrophage activation and promotes islet graft survival after intrahepatic islet transplantation.
Alpha-1 antitrypsin suppresses macrophage activation and promotes islet graft survival after intrahepatic islet transplantation.
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DOI：
10.1111/ajt.16342
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Gou W;Wang J;Song L;Kim DS;Cui W;Strange C;Wang H
α-1抗胰蛋白酶（AAT）在动物胰岛移植模型中具有保护作用。虽然AAT疗法的治疗效果目前正在临床试验中进行测试，但我们在临床相关的边缘性肝内人胰岛移植模型中研究了AAT保护的机制。在接受胰岛和AAT的受者中，68.9%（20/29）在移植后60天（PT）达到正常血糖，而仅接受胰岛的受者为35.7%（10/28）。AAT处理的小鼠在PT后即刻具有较低的炎性细胞因子血清水平。通过流式细胞术和RNA-seq转录谱分析证明，与对照组相比，在AAT处理的受体的肝脏中观察到减少的M1巨噬细胞。在体外，AAT通过抑制STAT 1磷酸化和iNOS产生来抑制IFN-γ诱导的M1巨噬细胞活化/极化。AAT抑制由细胞因子或死亡胰岛诱导的巨噬细胞活化，并因此导致胰岛细胞存活。在巨噬细胞耗竭小鼠模型中，肝脏中存在M1巨噬细胞导致移植物死亡。AAT通过抑制巨噬细胞活化，在人胰岛和NOD-SCID小鼠模型中保护移植的胰岛免于死亡和功能障碍。AAT的保护作用在主要错配的同种异体胰岛移植模型中得到证实。总之，AAT抑制肝巨噬细胞活化，有助于移植后移植物存活。
Alpha-1 antitrypsin (AAT) has protective functions in animal islet transplantation models. While the therapeutic effect of AAT therapy is currently being tested in clinical trials, we investigated the mechanism of AAT protection in a clinically relevant marginal intrahepatic human islet transplantation model. In recipients receiving islets and AAT, 68.9% (20/29) reached normoglycemia, compared to 35.7% (10/28) in those receiving islets only, at 60 days posttransplant (PT). AAT-treated mice had lower serum levels of inflammatory cytokines immediately PT. Reduced M1 macrophages were observed in livers of AAT-treated recipients compared to controls as evidenced by flow cytometry and RNA-seq transcriptional profiling analysis. In vitro AAT suppressed IFN-γ-induced M1 macrophage activation/polarization via suppression of STAT1 phosphorylation and iNOS production. AAT inhibits macrophage activation induced by cytokines or dying islets, and consequently leads to islet cell survival. In a macrophage depletion mouse model, the presence of M1 macrophages in the liver contributed to graft death. AAT, through suppressing macrophage activation, protected transplanted islets from death and dysfunction in the human islet and NOD-SCID mouse model. The protective effect of AAT was confirmed in a major mismatch allogeneic islet transplantation model. Taken together, AAT suppresses liver macrophage activation that contributes to graft survival after transplantation.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
巨噬细胞和骨炎症
影响因子：
6.6
作者：
Gu Q;Yang H;Shi Q
通讯作者：
Shi Q
影响因子：
2.2
作者：
GRAY, DWR;SUTTON, R;MORRIS, PJ
通讯作者：
MORRIS, PJ
DOI：
10.1111/ajt.14756
发表时间：
2018-07
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Berger M;Liu M;Uknis ME;Koulmanda M
通讯作者：
Koulmanda M
影响因子：
8.7
作者：
Gordon S;Plüddemann A;Martinez Estrada F
通讯作者：
Martinez Estrada F