Bottino R, Fernandez L A, Ricordi C, Lehmann R, Tsan M F, Oliver R, Inverardi L
Diabetes Research Institute, Cell Transplant Center, University of Miami School of Medicine, Florida 33136, USA.
Diabetes. 1998 Mar;47(3):316-23. doi: 10.2337/diabetes.47.3.316.
Early impairment of islet function and graft loss limit the success of allogeneic islet transplantation. Nonspecific inflammatory events occurring at the transplant site immediately after grafting, involving the production of cytokines and free radicals and sinusoidal endothelial cell (SEC) activation, may contribute to islet cell damage. To evaluate whether Kupffer cell inactivation would result in prolonged allograft survival in a model system of intrahepatic islet transplantation in rats, we systemically administered either gadolinium chloride (GdCl3) or dichloromethylene diphosphonate (Cl2MDP) to assess the effects of macrophage inactivation on rejection and on the release of proinflammatory molecules, as well as to assess the functional profile of SEC. The results obtained were compared with those observed in untreated, sham-injected animals and in rats receiving intraportal infusions of microbeads. Transient macrophage inhibition, particularly in hepatic Kupffer cells, is associated with significant prolongation of graft survival after intraportal islet allotransplantation (ITx) in rats: 7.2 days in the control group versus 11.9 days in the GdCl3 group (P < 0.01) and 15.6 days in the Cl2MDP group (P < 0.0006), respectively. Although systemic release of inflammatory mediators was observed only when islet transplantations were performed and it could be inhibited by macrophage-targeting treatments, perturbation of the functional profile of endothelial cells was also observed when microembolization was induced by the use of microbeads and could not be prevented by macrophage inhibition. These experiments provide evidence to support the concept that macrophages play a key role in early inflammatory events known to adversely affect islet engraftment and suggest that manipulation of nonspecific immune activation by inhibition of macrophage function may facilitate hepatic engraftment of islet allografts. The mechanisms mediating this effect are likely to include prevention of release of tumor necrosis factor-alpha, interleukin-1beta, and NO and interference with the rate of immune response to the islets.
胰岛功能的早期损害和移植物丢失限制了同种异体胰岛移植的成功。移植后立即在移植部位发生的非特异性炎症事件，包括细胞因子和自由基的产生以及肝血窦内皮细胞（SEC）的激活，可能导致胰岛细胞损伤。为了评估在大鼠肝内胰岛移植模型系统中，枯否细胞失活是否会导致同种异体移植物存活时间延长，我们系统性地给予氯化钆（GdCl3）或二氯亚甲基二膦酸盐（Cl2MDP），以评估巨噬细胞失活对排斥反应和促炎分子释放的影响，以及评估SEC的功能特征。将获得的结果与未治疗、假注射动物以及接受门静脉内微珠输注的大鼠中观察到的结果进行比较。短暂的巨噬细胞抑制，尤其是肝内枯否细胞的抑制，与大鼠门静脉内胰岛同种异体移植（ITx）后移植物存活时间的显著延长相关：对照组为7.2天，GdCl3组为11.9天（P < 0.01），Cl2MDP组为15.6天（P < 0.0006）。虽然仅在进行胰岛移植时观察到炎症介质的全身释放，并且可以通过靶向巨噬细胞的治疗来抑制，但在使用微珠诱导微栓塞时也观察到内皮细胞功能特征的扰动，并且不能通过巨噬细胞抑制来预防。这些实验提供了证据支持巨噬细胞在已知对胰岛植入有不利影响的早期炎症事件中起关键作用的概念，并表明通过抑制巨噬细胞功能来操纵非特异性免疫激活可能促进胰岛同种异体移植物在肝脏中的植入。介导这种效应的机制可能包括预防肿瘤坏死因子-α、白细胞介素-1β和一氧化氮的释放以及干扰对胰岛的免疫反应速率。
