Heme Oxygenase-1 Induction in Islet Cells Results in Protection From Apoptosis and Improved In Vivo Function After Transplantation
- Antonello Pileggi1,
- R. Damaris Molano1,
- Thierry Berney1,
- Pierre Cattan1,
- Caterina Vizzardelli1,
- Robert Oliver1,
- Christopher Fraker1,
- Camillo Ricordi1,
- Ricardo L. Pastori1,
- Fritz H. Bach2 and
- Luca Inverardi1
- 1Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida
- 2Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
Abstract
Transplantation of islets of Langerhans represents a viable therapeutic approach for the treatment of type 1 diabetes. Unfortunately, transplanted islets are susceptible to allogeneic recognition and rejection, recurrence of autoimmunity, and destruction by local inflammation at the site of implantation. The last of these phenomena might not only result in functional impairment and death of islet cells but could also contribute to amplifying the subsequent specific immune response. Induction of islet cell protection against inflammation could therefore be postulated to be a powerful means to improve overall graft fate. Heme oxygenase-1 (HO-1) has been described as an inducible protein capable of cytoprotection via radical scavenging and apoptosis prevention. The purpose of the present study was to analyze whether HO-1 upregulation in a β-cell line and in freshly isolated murine islets could result in protection from apoptosis and improve in vivo functional performance. HO-1 upregulation was induced reproducibly with protoporphyrins and was correlated with protection from apoptosis induced in vitro with proinflammatory cytokines or Fas engagement. Furthermore, in vivo HO-1 upregulation resulted in improved islet function in a model of marginal mass islet transplantation in rodents. Strategies aimed at inducing HO-1 upregulation might result in improved success in islet transplantation.
Footnotes
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Address correspondence and reprint requests to Luca Inverardi, MD, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136. E-mail: linverar{at}med.miami.edu.
Received for publication 29 January 2001 and accepted in revised form 30 May 2001.
F.H.B. has received consulting fees from Novartis.
P.C. is currently affiliated with the Department of Surgery, Saint Louis Hospital, Paris, France. C.V. is currently affiliated with the Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy.
CHX, cyclohexamide; CO, carbon monoxide; CoPP, cobaltic protoporphyrin IX chloride; FACS, fluorescence-activated cell sorter; FCS, fetal calf serum; FePP, ferriprotoporphyrin IX chloride; HBSS, Hanks’ balanced salt solution; HO-1, heme oxygenase-1; IEN, islet equivalent number; IFN-γ, interferon-γ; IL, interleukin; MT, median time; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PI, propidium iodide; RT, reverse transcription; STZ, streptozotocin; TNF-α, tumor necrosis factor-α; WB, Western blot.
