Anti-proinflammatory effects of sirolimus on human islet preparations

Atsuyoshi Mita, Camillo Ricordi, Atsushi Miki, Scott Barker, Ross Haertter, Yasuhiko Hashikura, Shin Ichi Miyagawa, George W Burke, Luca A Inverardi, Hirohito Ichii

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Abstract

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 β-cell viability, β-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 β-cell viability showed no significant differences, β-cell survival during culture significantly increased in impure sirolimus group when compared with the impure control group (P=0.015). Tumor necrosis factor-α, interleukin-1β, monocyte chemotactic protein-1, and macrophage inflammatory protein-1β production from the impure sirolimus group significantly decreased (P<0.05). Furthermore, tumor necrosis factor-α and macrophage inflammatory protein-1β 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 β-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.

Original languageEnglish
Pages (from-to)46-53
Number of pages8
JournalTransplantation
Volume86
Issue number1
DOIs
StatePublished - Jul 15 2008

Fingerprint

Sirolimus
Cell Survival
Macrophage Inflammatory Proteins
Islets of Langerhans Transplantation
Insulin
Islets of Langerhans
Tumor Necrosis Factor-alpha
Macrophages
Control Groups
Chemokine CCL2
Tacrolimus
Interleukin-1
Chemokines
Immunosuppression
Culture Media
Anti-Inflammatory Agents
Cell Culture Techniques
Steroids
Cytokines
Glucose

Keywords

  • Chemokine
  • Cytokine
  • Islet
  • Rapamycin
  • Transplantation

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Mita, A., Ricordi, C., Miki, A., Barker, S., Haertter, R., Hashikura, Y., ... Ichii, H. (2008). Anti-proinflammatory effects of sirolimus on human islet preparations. Transplantation, 86(1), 46-53. https://doi.org/10.1097/TP.0b013e31817c79c0

Anti-proinflammatory effects of sirolimus on human islet preparations. / Mita, Atsuyoshi; Ricordi, Camillo; Miki, Atsushi; Barker, Scott; Haertter, Ross; Hashikura, Yasuhiko; Miyagawa, Shin Ichi; Burke, George W; Inverardi, Luca A; Ichii, Hirohito.

In: Transplantation, Vol. 86, No. 1, 15.07.2008, p. 46-53.

Research output: Contribution to journalArticle

Mita, A, Ricordi, C, Miki, A, Barker, S, Haertter, R, Hashikura, Y, Miyagawa, SI, Burke, GW, Inverardi, LA & Ichii, H 2008, 'Anti-proinflammatory effects of sirolimus on human islet preparations', Transplantation, vol. 86, no. 1, pp. 46-53. https://doi.org/10.1097/TP.0b013e31817c79c0
Mita, Atsuyoshi ; Ricordi, Camillo ; Miki, Atsushi ; Barker, Scott ; Haertter, Ross ; Hashikura, Yasuhiko ; Miyagawa, Shin Ichi ; Burke, George W ; Inverardi, Luca A ; Ichii, Hirohito. / Anti-proinflammatory effects of sirolimus on human islet preparations. In: Transplantation. 2008 ; Vol. 86, No. 1. pp. 46-53.
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AU - Haertter, Ross

AU - Hashikura, Yasuhiko

AU - Miyagawa, Shin Ichi

AU - Burke, George W

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AU - Ichii, Hirohito

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N2 - 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 β-cell viability, β-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 β-cell viability showed no significant differences, β-cell survival during culture significantly increased in impure sirolimus group when compared with the impure control group (P=0.015). Tumor necrosis factor-α, interleukin-1β, monocyte chemotactic protein-1, and macrophage inflammatory protein-1β production from the impure sirolimus group significantly decreased (P<0.05). Furthermore, tumor necrosis factor-α and macrophage inflammatory protein-1β 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 β-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.

AB - 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 β-cell viability, β-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 β-cell viability showed no significant differences, β-cell survival during culture significantly increased in impure sirolimus group when compared with the impure control group (P=0.015). Tumor necrosis factor-α, interleukin-1β, monocyte chemotactic protein-1, and macrophage inflammatory protein-1β production from the impure sirolimus group significantly decreased (P<0.05). Furthermore, tumor necrosis factor-α and macrophage inflammatory protein-1β 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 β-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.

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