Johansson Helena, Lukinius Agneta, Moberg Lisa, Lundgren Torbjörn, Berne Christian, Foss Aksel, Felldin Marie, Källen Ragnar, Salmela Kaija, Tibell Annika, Tufveson Gunnar, Ekdahl Kristina Nilsson, Elgue Graciela, Korsgren Olle, Nilsson Bo
The Rudbeck Laboratory, University Hospital, 751 85 Uppsala, Sweden.
Diabetes. 2005 Jun;54(6):1755-62. doi: 10.2337/diabetes.54.6.1755.
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.
有充分迹象表明，在临床胰岛移植中只有一小部分移植物能成功植入。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）。在本研究中，我们发现用于胰岛移植的胰岛会产生跨膜形式和可变剪接形式的组织因子，并且膜结合形式会作为微粒释放，这些微粒通常与胰岛素和胰高血糖素颗粒相关。一种间接阻断两种形式组织因子的低分子量因子VIIa（FVIIa）抑制剂在体外被证明是一种消除IBMIR的有前景的药物。在9名共接受20次分离的人胰岛输注的患者中测量了凝血酶 - 抗凝血酶复合物（TAT）和FVIIa - 抗凝血酶复合物（FVIIa - AT）。输注后15 - 60分钟内，TAT和FVIIa - AT复合物均迅速增加。当初始TAT和FVIIa - AT水平与7天后C肽浓度的增加作图时，最初具有强烈IBMIR的患者在7天后胰岛素合成没有显著增加。总之，胰岛和培养基中存在的组织因子引发IBMIR，这会影响移植胰岛的功能。
