Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival
Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival
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DOI：
10.1073/pnas.1018366109
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发表时间：
2012-09-18
影响因子：
11.1
通讯作者：
Strom, Terry B.
中科院分区：
文献类型：
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作者：
Koulmanda, Maria;Bhasin, Manoj;Strom, Terry B.
如果不能改善弹性胰岛的植入，胰岛细胞移植的前景就不能完全实现。连续移植周围损伤后存活的胰岛边缘质量可能导致衰竭，从而导致不可接受的中期和长期移植物丢失率。因此，我们研究了α 1-抗胰蛋白酶（AAT）在同系非自身免疫性胰岛移植模型中的治疗效果。将少量同基因小鼠胰岛移植到非自身免疫性糖尿病宿主中，并在对照和AAT处理的宿主中分析胰岛功能。在未治疗的对照组中，边缘质量胰岛移植不能恢复正常。短期AAT治疗显著改善了结局。在移植后第3天，转录谱分析确定了AAT处理的宿主中1，184个差异表达的转录本。基于系统生物学的分析显示，AAT下调了炎症相关分子形成的调控中心（例如，例如，在一个实施例中，TNF-α、NF-κ B）。通过系统生物学分析得出的结论通过QRT-PCR和免疫组织学得到严格证实。这些数据表明，短期AAT治疗人类胰岛移植受体可能值得进行临床试验。
The promise of islet cell transplantation cannot be fully realized in the absence of improvements in engraftment of resilient islets. The marginal mass of islets surviving the serial peritransplant insults may lead to exhaustion and thereby contribute to an unacceptably high rate of intermediate and long-term graft loss. Hence, we have studied the effects of treatment with alpha 1-antitrypsin (AAT) in a syngeneic nonautoimmune islet graft model. A marginal number of syngeneic mouse islets were transplanted into nonautoimmune diabetic hosts and islet function was analyzed in control and AAT treated hosts. In untreated controls, marginal mass islet transplants did not restore euglycemia. Outcomes were dramatically improved by short-term AAT treatment. Transcriptional profiling identified 1,184 differentially expressed transcripts in AAT-treated hosts at 3 d posttransplantation. Systems-biology-based analysis revealed AAT down-regulated regulatory hubs formed by inflammation-related molecules (e. g., TNF-alpha, NF-kappa B). The conclusions yielded by the systems-biology analysis were rigorously confirmed by QRT-PCR and immunohistology. These data suggest that short-term AAT treatment of human islet transplant recipients may be worthy of a clinical trial.