Effects of immunosuppression on alpha and beta cell renewal in transplanted mouse islets.

AIMS/HYPOTHESIS: Immunosuppressive drugs used in human islet transplantation interfere with the balance between beta cell renewal and death, and thus may contribute to progressive graft dysfunction. We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. METHODS: C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4 weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. RESULTS: After 4 weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. CONCLUSIONS/INTERPRETATION: After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation.

Proteinases and proteinase inhibitors during the development of pulmonary fibrosis in rat.

Changes in the activities of several proteinases and their inhibitors were investigated during the development of bleomycin-induced pulmonary fibrosis in rat. Studies on the proteinase-anti-proteinase-ratio may contribute to the understanding of the mechanism of the development of pulmonary fibrosis and may help to develop therapeutic strategies to prevent tissue damage by proteolytic attack. In the acute inflammatory period the activity of metalloelastase in lung tissue increased by about 10-fold. The time course of changes in the activity of 72 kD gelatinase indicates that this gelatinase accounts at least partially for the elastolytic activity. Elastase inhibitory activity in lung tissue showed maxima at days 1 and 5 and high levels in the fibrotic phase. The increase of the elastase inhibitory activity at the beginning of the fibrotic period corresponds with elevated activity of alpha 2-macroglobulin. Alveolar fluid and alveolar macrophages did not contain elastase activity but contained high elastase inhibitory activity. During the period of chronic inflammation, the activities of the cathepsins L, B, H and S in lung tissue and in isolated alveolar macrophages were found to be strongly increased.