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Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection

BACKGROUND. Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone...

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Autores principales: van Alem, Carla M.A., Schmidbauer, Martina, Rong, Song, Derlin, Katja, Schmitz, Jessica, Bräsen, Jan H., Thorenz, Anja, Chen, Rongjun, Ruben, Jurjen M., Winter, Elizabeth M., Schilperoort, Maaike, Kooijman, Sander, Lalai, Reshma A., Metselaar, Josbert M., Klemann, Christian, Meier, Martin, van Kooten, Cees, Gueler, Faikah, Rotmans, Joris I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147400/
https://www.ncbi.nlm.nih.gov/pubmed/31929419
http://dx.doi.org/10.1097/TP.0000000000003060
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author van Alem, Carla M.A.
Schmidbauer, Martina
Rong, Song
Derlin, Katja
Schmitz, Jessica
Bräsen, Jan H.
Thorenz, Anja
Chen, Rongjun
Ruben, Jurjen M.
Winter, Elizabeth M.
Schilperoort, Maaike
Kooijman, Sander
Lalai, Reshma A.
Metselaar, Josbert M.
Klemann, Christian
Meier, Martin
van Kooten, Cees
Gueler, Faikah
Rotmans, Joris I.
author_facet van Alem, Carla M.A.
Schmidbauer, Martina
Rong, Song
Derlin, Katja
Schmitz, Jessica
Bräsen, Jan H.
Thorenz, Anja
Chen, Rongjun
Ruben, Jurjen M.
Winter, Elizabeth M.
Schilperoort, Maaike
Kooijman, Sander
Lalai, Reshma A.
Metselaar, Josbert M.
Klemann, Christian
Meier, Martin
van Kooten, Cees
Gueler, Faikah
Rotmans, Joris I.
author_sort van Alem, Carla M.A.
collection PubMed
description BACKGROUND. Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone (LP) facilitates local exposure to enhance its therapeutic effect. METHODS. Male BalbC recipients received renal allografts from male C57BL/6J donors. Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or LP intravenously on day 0, 3, and 6, or no additional treatment. Functional magnetic resonance imaging (fMRI) was performed on day 6 to study allograft perfusion and organs were retrieved on day 7 for further analysis. RESULTS. Staining of polyethylene-glycol-labeled liposomes and high performance liquid chromatography analysis revealed accumulation in the LP treated allograft. LP treatment induced the expression of glucocorticoid responsive gene Fkbp5 in the allograft. Flow-cytometry of allografts revealed liposome presence in CD45(+) cells, and reduced numbers of F4/80(+) macrophages, and CD3(+) T-lymphocytes upon LP treatment. Banff scoring showed reduced interstitial inflammation and tubulitis and fMRI analysis revealed improved allograft perfusion in LP versus NA mice. CONCLUSIONS. Liposomal delivery of prednisolone improved renal bio-availability, increased perfusion and reduced cellular infiltrate in the allograft, when compared with conventional prednisolone. Clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection.
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spelling pubmed-71474002020-04-24 Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection van Alem, Carla M.A. Schmidbauer, Martina Rong, Song Derlin, Katja Schmitz, Jessica Bräsen, Jan H. Thorenz, Anja Chen, Rongjun Ruben, Jurjen M. Winter, Elizabeth M. Schilperoort, Maaike Kooijman, Sander Lalai, Reshma A. Metselaar, Josbert M. Klemann, Christian Meier, Martin van Kooten, Cees Gueler, Faikah Rotmans, Joris I. Transplantation Original Basic Science—General BACKGROUND. Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone (LP) facilitates local exposure to enhance its therapeutic effect. METHODS. Male BalbC recipients received renal allografts from male C57BL/6J donors. Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or LP intravenously on day 0, 3, and 6, or no additional treatment. Functional magnetic resonance imaging (fMRI) was performed on day 6 to study allograft perfusion and organs were retrieved on day 7 for further analysis. RESULTS. Staining of polyethylene-glycol-labeled liposomes and high performance liquid chromatography analysis revealed accumulation in the LP treated allograft. LP treatment induced the expression of glucocorticoid responsive gene Fkbp5 in the allograft. Flow-cytometry of allografts revealed liposome presence in CD45(+) cells, and reduced numbers of F4/80(+) macrophages, and CD3(+) T-lymphocytes upon LP treatment. Banff scoring showed reduced interstitial inflammation and tubulitis and fMRI analysis revealed improved allograft perfusion in LP versus NA mice. CONCLUSIONS. Liposomal delivery of prednisolone improved renal bio-availability, increased perfusion and reduced cellular infiltrate in the allograft, when compared with conventional prednisolone. Clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection. Lippincott Williams & Wilkins 2020-04 2020-03-31 /pmc/articles/PMC7147400/ /pubmed/31929419 http://dx.doi.org/10.1097/TP.0000000000003060 Text en Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Original Basic Science—General
van Alem, Carla M.A.
Schmidbauer, Martina
Rong, Song
Derlin, Katja
Schmitz, Jessica
Bräsen, Jan H.
Thorenz, Anja
Chen, Rongjun
Ruben, Jurjen M.
Winter, Elizabeth M.
Schilperoort, Maaike
Kooijman, Sander
Lalai, Reshma A.
Metselaar, Josbert M.
Klemann, Christian
Meier, Martin
van Kooten, Cees
Gueler, Faikah
Rotmans, Joris I.
Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection
title Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection
title_full Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection
title_fullStr Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection
title_full_unstemmed Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection
title_short Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection
title_sort liposomal delivery improves the efficacy of prednisolone to attenuate renal inflammation in a mouse model of acute renal allograft rejection
topic Original Basic Science—General
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147400/
https://www.ncbi.nlm.nih.gov/pubmed/31929419
http://dx.doi.org/10.1097/TP.0000000000003060
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