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Effects of immunosuppression on proliferation in transplanted islets

Christian Krautz^1,2, Steffen Wolk², Anja Steffen², Klaus-Peter Knoch², Uta Ceglarek³, Hans-Detlev Saeger¹, Michele Solimena², Stephan Kersting^1,2

¹General, Thoracic and Vascular Surgery; ²Paul Langerhans Institute, University of Dresden, Dresden; ³Institute of Laboratory Medicine, University of Leipzig, Leipzig; Germany

Background: The antiproliferative effects of immunosuppressive drugs such as sirolimus and tacrolimus used in human islet transplantation interfere with the capacity of β cells to balance cell renewal and cell loss. This feature may be an important contributor to progressive graft dysfunction in islet transplant recipients over time. We analyzed the influence of different immunosuppressants on α and β cell proliferation and transplant outcome following syngeneic β cell transplantation in mice.

Methods: Syngeneic islets (300 IP) were injected into the right liver lobes of C57BL/6 diabetic recipients. Osmotic pumps filled with bromodeoxyuridine (BrdU) (control) or BrdU and an immunosuppressant [tacrolimus, sirolimus, everolimus, or mycophenolate mofetil (MMF)] were implanted. Glycemic control was assessed using glucose tolerance tests. After four weeks, proliferation of α and β cells was detected by BrdU incorporation. In addition, fractional β cell area and average β cell size was determined by morphometric analysis.

Results: The average blood glucose levels were significantly higher in all treatment groups compared to controls. Glucose tolerance was improved only in control animals (P = 0.009). The fractional β cell area and β cell proliferation in MMF-treated mice were comparable to control mice (P = 0.66). In contrast, treatment with everolimus and sirolimus led to a significant reduction in β cell proliferation and fractional β cell area. While transplanted β cells from animals treated with tacrolimus also presented a reduced replication rate (P = 0.023), the fractional β cell area was not affected compared to untreated controls (P = 0.72).

Conclusions: Our results demonstrate that the β cells of transplanted islets have a strong capacity for self-renewal when not affected by immunosuppression or immune assault. In contrast to other immunosuppressants, MMF does not affect β cell replication and fractional β cell area; therefore, its use may lead to improved long-term results in islet transplantation.