Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought t...

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Autores principales:	Ruth E. McDowell PhD, Khawla F. Ali MD, Saloni Lad MA, Vicente T. San Martin MD, Rita Bottino PhD, Matthew Walsh MD, Tyler Stevens MD, William Wilke MD, John P. Kirwan PhD, Betul Hatipoglu MD
Formato:	article
Lenguaje:	EN
Publicado:	SAGE Publishing 2021
Materias:	Medicine R
Acceso en línea:	https://doaj.org/article/2badc91744434309a0b5ca95fc084d53
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spelling	oai:doaj.org-article:2badc91744434309a0b5ca95fc084d532021-11-11T00:33:34ZBioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation1555-389210.1177/09636897211057440https://doaj.org/article/2badc91744434309a0b5ca95fc084d532021-11-01T00:00:00Zhttps://doi.org/10.1177/09636897211057440https://doaj.org/toc/1555-3892The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients ( n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients ( n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients ( P =0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT ( P =0.01, R 2 =0.489 and P =0.03, R 2 =0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration ( P <0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.Ruth E. McDowell PhDKhawla F. Ali MDSaloni Lad MAVicente T. San Martin MDRita Bottino PhDMatthew Walsh MDTyler Stevens MDWilliam Wilke MDJohn P. Kirwan PhDBetul Hatipoglu MDSAGE PublishingarticleMedicineRENCell Transplantation, Vol 30 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R
spellingShingle	Medicine R Ruth E. McDowell PhD Khawla F. Ali MD Saloni Lad MA Vicente T. San Martin MD Rita Bottino PhD Matthew Walsh MD Tyler Stevens MD William Wilke MD John P. Kirwan PhD Betul Hatipoglu MD Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation
description	The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients ( n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients ( n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients ( P =0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT ( P =0.01, R 2 =0.489 and P =0.03, R 2 =0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration ( P <0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.
format	article
author	Ruth E. McDowell PhD Khawla F. Ali MD Saloni Lad MA Vicente T. San Martin MD Rita Bottino PhD Matthew Walsh MD Tyler Stevens MD William Wilke MD John P. Kirwan PhD Betul Hatipoglu MD
author_facet	Ruth E. McDowell PhD Khawla F. Ali MD Saloni Lad MA Vicente T. San Martin MD Rita Bottino PhD Matthew Walsh MD Tyler Stevens MD William Wilke MD John P. Kirwan PhD Betul Hatipoglu MD
author_sort	Ruth E. McDowell PhD
title	Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation
title_short	Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation
title_full	Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation
title_fullStr	Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation
title_full_unstemmed	Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation
title_sort	bioenergetics of islet preparations in a pilot clinical trial of peri-transplant hydroxychloroquine for autologous islet transplantation
publisher	SAGE Publishing
publishDate	2021
url	https://doaj.org/article/2badc91744434309a0b5ca95fc084d53
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Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation

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