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Open Access Activation of Peroxisome Proliferator-Activated Receptor γ Prolongs Islet Allograft Survival

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Abstract:

Exposing donor mice to carbon monoxide (CO) protects transplanted islet allografts from immune rejection after transplantation (referred as the “donor” effect). In an attempt to understand the mechanisms of the donor effect of CO, we found that donor treatment with CO upregulates expression of peroxisome proliferator-activated receptor γ (PPARγ), a transcriptional regulator, in isolated islets. In this study, we evaluated whether PPARγ contributes to the survival and function of transplanted islets and whether PPARγ mediates the protective effect of CO in a major mismatch islet allogeneic transplantation model. BALB/c (H-2d) islets in which PPARγ activity was induced by its agonists, 15-deoxy-Δ12-14-prostaglandin J2 (15d-PGJ2) or troglitazone were transplanted into C57BL/6 (H-2b) recipients that had been rendered diabetic by streptozotocin (STZ). Blood glucose levels of recipients were monitored to determine the function of transplanted islets. Our data indicated that PPARγ activation in islets led to a high percentage of BALB/c islets survived long-term in C57BL/6 recipients. Activation of PPARγ in the donor suppresses expressions of proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) in transplanted islets. Blocking PPARγ activity by its antagonist, GW9662, abrogated the donor effect of CO in vivo and in vitro. Our data demonstrate that PPARγ plays a critical role in the survival and function of transplanted islets after transplantation in the recipient. The protective effects of CO are at least in part mediated by PPARγ.

Keywords: Allograft survival; Carbon monoxide; Islet transplantation; Peroxisome proliferator-activated receptor γ (PPARγ)

Document Type: Research Article

DOI: https://doi.org/10.3727/096368911X637399

Affiliations: Department of Surgery, Medical University of South Carolina, Charleston, SC, USA

Publication date: 2012-10-01

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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