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Identification des mécanismes cellulaires et moléculaires à l'origine de la perte précoce des îlots pancréatiques au cours de la transplantation

Abstract : From isolation of pancreatic islets to their implantation, the inflammation is ubiquitous in the pancreatic islet transplantation. Maintaining a controlled inflammation is essential to preserve the survival of the graft and the functionality in the short and long term. The objective of this work is to identify precisely the inflammatory mechanisms behind the early loss of islets and identify therapeutic targets to reduce these inflammatory reactions. We have demonstrated that culture conditions induce reactions causing the development of a specific proinflammatory and pro-oxydant phenotype islet. This induction is characterized by an increase in the secretion of cytokines, chemokines pro-inflammatory activation pathways of inflammation Toll-like receptors (TLRs) -dependent and generation of reactive oxygen species (ROS). However, this process can be prevented by the activation of Heme oxygenase-1 (HO-1), an antioxidant and anti-inflammatory enzyme.By studying the inflammatory responses in an animal model of transplantation mimicking the conditions of human transplantation, we demonstrated that a change of plasma mediators of inflammation and liver proteome occurs 12 hours after transplantation. Furthermore, these results are associated with infiltration of the islets by immune cells which organizes 12 hours after transplantation. We also determined the anti-inflammatory role of rapamycin (an immunomodulatory drug) on the islets and macrophages in vitro. We have thus demonstrated that the use of rapamycin with the establishment of a pre-treatment of islets and recipient before transplantation could be considered. These studies have characterized the inflammatory mechanisms implemented immediately before and after transplantation. Thus, these data provide new therapeutic approaches that can prevent and / or reduce inflammation during pancreatic islet transplantation
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https://tel.archives-ouvertes.fr/tel-00806576
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Submitted on : Tuesday, April 2, 2013 - 1:08:12 AM
Last modification on : Tuesday, January 18, 2022 - 12:26:54 PM
Long-term archiving on: : Wednesday, July 3, 2013 - 4:03:21 AM

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Kevin Vivot. Identification des mécanismes cellulaires et moléculaires à l'origine de la perte précoce des îlots pancréatiques au cours de la transplantation. Médecine humaine et pathologie. Université de Strasbourg, 2012. Français. ⟨NNT : 2012STRAJ062⟩. ⟨tel-00806576⟩

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