title: Rapamycin does not adversely affect intrahepatic islet engraftment in mice and improves early islet engraftment in humans.
abstract: 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.
  
  
  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 recipients (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.
  
  
  CONCLUSIONS
  Rapamycin does not adversely affect intrahepatic islet engraftment in the mouse, and potentially improves islet engraftment in humans by an anti-inflammatory mechanism.
authors.affiliation: Beta Cell Biology Unit, San Raffaele Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Melzi
authors.forename: Paola
authors.initials: P
authors.lastname: Maffi
authors.forename: Rita
authors.initials: R
authors.lastname: Nano
authors.forename: Valeria
authors.initials: V
authors.lastname: Sordi
authors.forename: Alessia
authors.initials: A
authors.lastname: Mercalli
authors.forename: Marina
authors.initials: M
authors.lastname: Scavini
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
mesh_terms: D000328:Adult; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008099:Liver; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology*; D013045:Species Specificity; D013997:Time Factors; D016042:Transplantation, Heterotopic / Q000379:methods*
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus