Effects of immunosuppressive drugs on in vitro neogenesis of human islets: mycophenolate mofetil inhibits the proliferation of ductal cells.

Assuming that neogenesis contributes to long-term function of islet grafts, it is important to study the effects of immunosuppressive drugs on precursor cell proliferation and differentiation. We examined the effects of low-dose immunosuppressive drugs on these processes in vitro. Immunosuppressive drugs, including sirolimus, tacrolimus, mycophenolate mofetil (MMF), daclizumab and their combinations were tested in parallel culture wells through either the expansion phase (5-7 days) or the entire culture period (4-5 weeks). MMF, alone or in combination with sirolimus or tacrolimus, severely hampered duct-cell proliferation by 8-fold during the expansion period, and significantly reduced the total DNA content by about 40% after 5-week culture. After 4-5 week exposure to different drugs, only sirolimus and daclizumab showed no adverse effects on insulin content, whereas significant reductions of 30-60% in insulin content were seen in all other experimental groups. Only tacrolimus decreased the insulin content per DNA, as well as the proportion of insulin-positive cells. In conclusion, MMF has a potent inhibitory effect on neogenesis primarily through an antiproliferative effect on the precursors, whereas tacrolimus mainly affects beta-cell differentiation. Sirolimus and daclizumab have no adverse effects on these parameters. The immunosuppressive protocol may be an important determinant of long-term clinical islet graft function.