de Vos Paul, de Haan Bart J, de Haan Aalzen, van Zanten Jacoba, Faas Marijke M
Transplantation Biology and Immunoendocrinology, Department of Pathology and Laboratory Medicine, Section of Medical Biology, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
Cell Transplant. 2004;13(5):515-24. doi: 10.3727/000000004783983738.
Graft function of encapsulated islets is restricted in spite of the fact that inflammatory responses against capsules are limited to a portion less than 10%. It has been shown that dysfunction is accompanied by a gradual decrease in the glucose-induced insulin response (GIIR), a hyperproliferation of islet cells, and gradual necrosis. Also, limited survival is associated with the presence of macrophages in the overgrowth. In the present study, we investigate whether macrophages are the inducers of dysfunction of encapsulated grafts. Four weeks after successful transplantation of microencapsulated rat allografts we determined the GIIR, the rate of islet cell replication, and islet cell death. Also, we quantified the number of macrophages on the overgrown capsules. This assessment was applied to set up an in vitro coculture system of macrophages and encapsulated islets. We retrieved 93 +/- 6.2% of the capsules of which 9.2 +/- 0.3% was overgrown. The GIIR of the retrieved nonovergrown islets was reduced when compared with freshly encapsulated islets. The replication rate of the retrieved islet cells was eightfold higher than in the normal pancreas. Apoptosis was rarely observed but 37 +/- 4% of the total islet surface was composed of necrosis. We found a mean of 1542 +/- 217 macrophages per capsule. Coculture of 1500 NR8383 macrophages per encapsulated islets induced a substantial reduction in GIIR but a decrease instead of increase in replication. Necrosis was restricted to 13 +/- 1.3% of the islet cells and was not increased by the presence of macrophages. Our observations indicate that we should focus on reduction of macrophage activation and on improving the nutrition of encapsulated islets to prevent islet cell death.
尽管对胶囊的炎症反应仅限于不到10%的部分，但封装胰岛的移植功能仍然受到限制。研究表明，功能障碍伴随着葡萄糖诱导的胰岛素反应（GIIR）逐渐降低、胰岛细胞过度增殖和逐渐坏死。此外，有限的存活与过度生长部位巨噬细胞的存在有关。在本研究中，我们调查巨噬细胞是否是封装移植物功能障碍的诱导因素。在微囊化大鼠同种异体移植物成功移植四周后，我们测定了GIIR、胰岛细胞复制率和胰岛细胞死亡情况。此外，我们对过度生长的胶囊上的巨噬细胞数量进行了定量。该评估用于建立巨噬细胞与封装胰岛的体外共培养系统。我们回收了93±6.2%的胶囊，其中9.2±0.3%过度生长。与新鲜封装的胰岛相比，回收的未过度生长的胰岛的GIIR降低。回收的胰岛细胞的复制率比正常胰腺高八倍。很少观察到细胞凋亡，但坏死占胰岛总表面积的37±4%。我们发现每个胶囊平均有1542±217个巨噬细胞。每个封装胰岛与1500个NR8383巨噬细胞共培养导致GIIR大幅降低，但复制减少而非增加。坏死仅限于13±1.3%的胰岛细胞，且巨噬细胞的存在并未使其增加。我们的观察结果表明，我们应专注于减少巨噬细胞活化并改善封装胰岛的营养，以防止胰岛细胞死亡。
