Moberg Lisa
Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Sweden.
Ups J Med Sci. 2005;110(1):17-55. doi: 10.3109/2000-1967-181.
Clinical islet transplantation is an emerging procedure to cure type 1 diabetes. The graft is implanted by infusion into the liver through the portal vein. A major obstacle that still needs to be overcome is the requirement for islets from multiple donors to achieve insulin independence. An innate inflammatory reaction, the IBMIR, is elicited when islets are exposed to blood. The IBMIR has been described as a clotting reaction culminating in disruption of islet morphology and is a plausible cause for loss of tissue during the early post-transplant period. In this thesis, the underlying mechanisms of the IBMIR were characterized. The IBMIR was for the first time demonstrated in patients undergoing an islet transplant, and a number of clinically applicable strategies to limit this reaction were identified. The thrombin inhibitor melagatran completely blocked the IBMIR in an in vitro tubing blood loop system, indicating that thrombin is the driving force in the reaction. Interestingly, islets were shown to produce and secrete tissue factor (TF), the physiological trigger of coagulation. Inactivated FVIIa, a specific inhibitor of TF, successfully blocked initiation of the IBMIR. An alternative approach to limit the IBMIR was to pre-treat islets in culture prior to transplantation. Nicotinamide added to the culture medium effectively decreased the level of TF in human islets. Infiltration of immune cells, also a part of the IBMIR, was characterized in detail. The predominant cell types infiltrating the islets were neutrophilic granulocytes and, to a lesser degree, monocytes. Both cell types may exert direct cytotoxic effects, and the antigen-presenting monocytes may also be important for directing the specific immune system to the site of inflammation. These findings have provided new insight into the nature of the IBMIR and offer several new strategies to improve the outcome of clinical islet transplantation.
临床胰岛移植是一种用于治疗1型糖尿病的新兴方法。通过门静脉将移植物输注到肝脏中进行植入。仍需克服的一个主要障碍是需要来自多个供体的胰岛才能实现胰岛素自主分泌。当胰岛暴露于血液中时，会引发一种先天性炎症反应，即胰岛植入后早期炎症反应（IBMIR）。IBMIR被描述为一种凝血反应，最终导致胰岛形态破坏，并且是移植后早期组织丢失的一个可能原因。在本论文中，对IBMIR的潜在机制进行了表征。首次在接受胰岛移植的患者中证实了IBMIR，并确定了一些临床适用的限制这种反应的策略。凝血酶抑制剂美拉加群在体外管道血循环系统中完全阻断了IBMIR，表明凝血酶是该反应的驱动力。有趣的是，胰岛被证明能产生并分泌组织因子（TF），即凝血的生理触发因子。灭活的FVIIa，一种TF的特异性抑制剂，成功地阻断了IBMIR的起始。另一种限制IBMIR的方法是在移植前对培养中的胰岛进行预处理。添加到培养基中的烟酰胺有效地降低了人胰岛中TF的水平。免疫细胞浸润也是IBMIR的一部分，对此进行了详细表征。浸润胰岛的主要细胞类型是嗜中性粒细胞，其次是单核细胞。这两种细胞类型都可能发挥直接的细胞毒性作用，并且作为抗原呈递细胞的单核细胞对于将特异性免疫系统引导至炎症部位也可能很重要。这些发现为IBMIR的本质提供了新的见解，并提供了几种改善临床胰岛移植结果的新策略。
