BACKGROUND: Sirolimus plays a critical role in facilitating steroid-free immunosuppression, in conjunction with low dose tacrolimus, in current islet transplantation. Although several studies have investigated the effects of sirolimus on islet cells, conflicting results have been reported. In this study, we assessed the effects of sirolimus supplementation in culture media on human islet preparations, focusing on the anti-proinflammatory aspects. METHODS: Human islet preparations were divided into four groups: pure (purity >90%) sirolimus (30 ng/mL); pure control (0 ng/mL); impure (purity 40%-60%) sirolimus; and impure control. All groups were cultured for 3 days and assessed regarding glucose stimulated insulin release, fractional beta-cell viability, beta-cell, and macrophage content. Cytokine and chemokine production from islet preparations and sorted pancreatic ductal cells were also examined. RESULTS: Stimulated insulin release in the impure sirolimus group was significantly increased (P=0.024), as previously reported. Although fractional beta-cell viability showed no significant differences, beta-cell survival during culture significantly increased in impure sirolimus group when compared with the impure control group (P=0.015). Tumor necrosis factor-alpha, interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-1beta production from the impure sirolimus group significantly decreased (P<0.05). Furthermore, tumor necrosis factor-alpha and macrophage inflammatory protein-1beta production from sorted ductal cells significantly decreased in the sirolimus group (P<0.05). The number of macrophages contained in islet preparations significantly decreased in the impure sirolimus group when compared with the impure control group (P<0.05). CONCLUSIONS: Sirolimus improved not only stimulated insulin release, but also beta-cell survival during culture. The antiinflammatory effects of sirolimus also appear beneficial to islet cells in culture and may be a useful strategy in improving islet transplantation outcomes.
BACKGROUND:Sirolimus plays a critical role in facilitating steroid-free immunosuppression, in conjunction with low dose tacrolimus, in current islet transplantation. Although several studies have investigated the effects of sirolimus on islet cells, conflicting results have been reported. In this study, we assessed the effects of sirolimus supplementation in culture media on human islet preparations, focusing on the anti-proinflammatory aspects. METHODS:Human islet preparations were divided into four groups: pure (purity >90%) sirolimus (30 ng/mL); pure control (0 ng/mL); impure (purity 40%-60%) sirolimus; and impure control. All groups were cultured for 3 days and assessed regarding glucose stimulated insulin release, fractional beta-cell viability, beta-cell, and macrophage content. Cytokine and chemokine production from islet preparations and sorted pancreatic ductal cells were also examined. RESULTS: Stimulated insulin release in the impure sirolimus group was significantly increased (P=0.024), as previously reported. Although fractional beta-cell viability showed no significant differences, beta-cell survival during culture significantly increased in impure sirolimus group when compared with the impure control group (P=0.015). Tumor necrosis factor-alpha, interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-1beta production from the impure sirolimus group significantly decreased (P<0.05). Furthermore, tumor necrosis factor-alpha and macrophage inflammatory protein-1beta production from sorted ductal cells significantly decreased in the sirolimus group (P<0.05). The number of macrophages contained in islet preparations significantly decreased in the impure sirolimus group when compared with the impure control group (P<0.05). CONCLUSIONS:Sirolimus improved not only stimulated insulin release, but also beta-cell survival during culture. The antiinflammatory effects of sirolimus also appear beneficial to islet cells in culture and may be a useful strategy in improving islet transplantation outcomes.
Authors: Niraj M Desai; John A Goss; Shaoping Deng; Bryan A Wolf; Eileen Markmann; Maral Palanjian; Angela P Shock; Sue Feliciano; F Charles Brunicardi; Clyde F Barker; Ali Naji; James F Markmann Journal: Transplantation Date: 2003-12-15 Impact factor: 4.939
Authors: C J March; B Mosley; A Larsen; D P Cerretti; G Braedt; V Price; S Gillis; C S Henney; S R Kronheim; K Grabstein Journal: Nature Date: 1985 Jun 20-26 Impact factor: 49.962
Authors: Iris Lee; Liqing Wang; Andrew D Wells; Qunrui Ye; Rongxiang Han; Martin E Dorf; William A Kuziel; Barrett J Rollins; Lieping Chen; Wayne W Hancock Journal: J Immunol Date: 2003-12-15 Impact factor: 5.422
Authors: James F Markmann; Shaoping Deng; Xiaolun Huang; Niraj M Desai; Ergun H Velidedeoglu; Chengyang Lui; Adam Frank; Eileen Markmann; Maral Palanjian; Kenneth Brayman; Bryan Wolf; Ewan Bell; Marko Vitamaniuk; Nicolai Doliba; Franz Matschinsky; Clyde F Barker; Ali Naji Journal: Ann Surg Date: 2003-06 Impact factor: 12.969
Authors: A Mita; C Ricordi; S Messinger; A Miki; R Misawa; S Barker; R D Molano; R Haertter; A Khan; S Miyagawa; A Pileggi; L Inverardi; R Alejandro; B J Hering; H Ichii Journal: Cell Transplant Date: 2010-08-17 Impact factor: 4.064
Authors: Yong Wang; Joshua E Mendoza-Elias; Meirigeng Qi; Tricia A Harvat; Sang Joon Ahn; Dongyoung Lee; Diana Gutierrez; Hyojin Jeon; Daniel Paushter; José Oberholzer Journal: Biochem Res Int Date: 2012-05-07