Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation
Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation
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DOI：
10.2337/diabetes.54.6.1755
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发表时间：
2005-06-01
期刊：
影响因子：
7.7
通讯作者：
Nilsson, B
中科院分区：
文献类型：
--
作者：
Johansson, H;Lukinius, A;Nilsson, B
有强有力的迹象表明，在临床胰岛移植中，只有一小部分移植物成功植入。一种解释可能是由内分泌细胞产生的组织因子引发的即时血液介导的炎症反应(IBMIR)。在目前的研究中，我们证明了用于胰岛移植的胰岛以跨膜和交替剪接的形式产生组织因子，并且膜结合的形式被释放为通常与胰岛素和胰高血糖素颗粒相关的微粒。一种间接阻断这两种组织因子的低分子质量因子VIIa(FVIIa)抑制剂在体外被证明是一种有前途的消除IBMIR的药物。测定了9例患者的凝血酶-抗凝血酶复合体(TAT)和FVIIa-抗凝血酶复合体(FVIIa-AT)，这些患者共接受了20个人胰岛的输注。TAT和FVIIa-AT复合体在输注后15-60分钟内均迅速升高。当最初的TAT和FVIIa-AT水平与7天后C肽浓度的增加相比较时，最初IBMIR较强的患者在7天后胰岛素合成没有显著增加。综上所述，组织因子同时存在于胰岛和培养液中，引起IBMIR，影响移植胰岛的功能。
There are strong indications that only a small fraction of grafts successfully engraft in clinical islet transplantation. One explanation may be the instant blood-mediated inflammatory reaction (IBMIR) elicited by tissue factor, which is produced by the endocrine cells. In the present study, we show that islets intended for islet transplantation produce tissue factor in both the transmembrane and the alternatively spliced form and that the membrane-bound form is released as microparticles often associated with both insulin and glucagon granules. A low-molecular mass factor VIIa (FVIIa) inhibitor that indirectly blocks both forms of tissue factor was shown in vitro to be a promising drug to eliminate the IBMIR. Thrombin-antithrombin complex (TAT) and FVIIa-antithrombin complex (FVIIa-AT) were measured in nine patients who together received 20 infusions of isolated human islets. Both the TAT and FVIIa-AT complexes increased rapidly within 15-60 min after infusion. When the initial TAT and FVIIa-AT levels were plotted against the increase in C-peptide concentration after 7 days, patients with an initially strong IBMIR showed no significant increase in insulin synthesis after 7 days. In conclusion, tissue factor present in both the islets and the culture medium and elicits IBMIR, which affects the function of the transplanted islets.