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Research Paper

Rapamycin does not adversely affect intrahepatic islet engraftment in mice and improves early islet engraftment in humans

Raffaella Melzi, Paola Maffi, Rita Nano, Valeria Sordi, Alessia Mercalli, Marina Scavini, Antonio Secchi, Ezio Bonifacio and Lorenzo Piemonti

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Objective: In this study we examined the effect of rapamycin (RAPA), a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function in vivo.
Methods and results: Diabetic C57BL/6 or BALB/C recipient mice were transplanted with 350 syngeneic islets through the portal vein (PV-Tx; C57BL/6 n = 60; BALB/C n = 22) and treated with once-daily oral RAPA (1 mg/kg) or vehicle. No differences in post-transplant blood glucose concentrations and glucose tolerance were observed between RAPA- and vehicle-treated mice. The impact of RAPA on human islet engraftment was assessed in 10 patients with type 1 diabetes treated with
0.1 mg/kg/day rapamycin before islet transplantation. Compared to non pre-treated islet transplant recipents (n = 12), RAPA pre-treated patients had increased blood RAPA concentrations (p = 0.006) and fasting C-peptide concentrations (p = 0.005) in the two weeks post-transplant. RAPA pre-treatment was associated with a reduction in chemokines CCL2 and CCL3 concentrations pre-transplant (p < 0.01), and a dampened chemokine response (p = 0.005) post-transplant. Concordantly, in vitro RAPA inhibited the secretion of CCL2 and CCL3 by monocytes.
Conclusion: Rapamycin does not adversely affect intrahepatic islet engraftment in the mouse, and potentially improves islet engraftment in humans by an anti-inflammatory mechanism.

Authors

Raffaella Melzi

Beta Cell Biology Unit, San Raffaele Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy

Paola Maffi

Transplant Unit, Department of Medicine, San Raffaele Scientific Institute, Milan, Italy

Rita Nano

Beta Cell Biology Unit, San Raffaele Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy

Valeria Sordi

Beta Cell Biology Unit, San Raffaele Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy

Alessia Mercalli

Beta Cell Biology Unit, San Raffaele Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy

Marina Scavini

Beta Cell Biology Unit, San Raffaele Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy

Antonio Secchi

Transplant Unit, Department of Medicine, San Raffaele Scientific Institute, Milan, Italy

Ezio Bonifacio

Dresden University of Technology, Center for Regenerative Therapies Dresden, Dresden, Germany

Lorenzo Piemonti Corresponding author: piemonti.lorenzo@hsr.it

Beta Cell Biology Unit, San Raffaele Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.