CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection

CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection

Adenosine triphosphate (ATP), an essential metabolic energy source, is released following cell apoptosis or necrosis. It acts as a damage-associated molecule pattern to stimulate innate immune cells. The ectonucleotidase CD39 regulates immune activation by hydrolysis of extracellular ATP. We have sh...

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Main Authors: Yoshida, Osamu, Dou, Lei, Kimura, Shoko, Yokota, Shinichiro, Isse, Kumiko, Robson, Simon C., Geller, David A., Thomson, Angus W.
Format: Online
Language:English
Published: 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368493/
id pubmed-4368493
recordtype oai_dc
spelling pubmed-43684932016-03-01 CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection Yoshida, Osamu Dou, Lei Kimura, Shoko Yokota, Shinichiro Isse, Kumiko Robson, Simon C. Geller, David A. Thomson, Angus W. Article Adenosine triphosphate (ATP), an essential metabolic energy source, is released following cell apoptosis or necrosis. It acts as a damage-associated molecule pattern to stimulate innate immune cells. The ectonucleotidase CD39 regulates immune activation by hydrolysis of extracellular ATP. We have shown previously that CD39 expression by donor livers helps protect syngeneic grafts with extended (24 hr) cold preservation time from ischemia reperfusion injury. Given its immune regulatory properties, we hypothesized that CD39 expression in donor livers might modulate transplant tolerance that occurs following mouse allogeneic liver transplantation (LTx). Livers from C57BL/6 (B6) wild-type (WT) or CD39 KO mice were transplanted into normal C3H recipients with minimal (approximately 1 hr) cold ischemia. Serum alanine aminotransferase levels at day 4 post LTx were significantly higher in animals given CD39KO compared with WT livers. Moreover, IFN-γ production by liver-infiltrating CD8+ T cells at day 4 was significantly higher in CD39KO than in WT grafts. Furthermore, splenic T cells from CD39KO liver recipients exhibited greater proliferative responses to donor alloantigens than those from mice given WT grafts. By contrast, there was a concomitant significant reduction in the frequency of regulatory T cells (Treg) in CD39KO than in WT livers. Whereas WT liver allografts survived > 100 days, no CD39KO grafts survived beyond 40 days (median survival time [MST]: WT: >100 days vs CD39KO: 8 days; p<0.01). In addition, soluble CD39 administration significantly prolonged CD39KO liver allograft survival (MST: 27.5 days). These novel data suggest that CD39 expression in liver allografts modulates tissue injury, inflammation, anti-donor effector T cell responses and Treg infiltration and can suppress transplant rejection. 2015-02-07 2015-03 /pmc/articles/PMC4368493/ /pubmed/25661084 http://dx.doi.org/10.1016/j.trim.2015.01.003 Text en © 2015 Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc/4.0/ This manuscript version is made available under the CC BY-NC-ND 4.0 license.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Yoshida, Osamu
Dou, Lei
Kimura, Shoko
Yokota, Shinichiro
Isse, Kumiko
Robson, Simon C.
Geller, David A.
Thomson, Angus W.
spellingShingle Yoshida, Osamu
Dou, Lei
Kimura, Shoko
Yokota, Shinichiro
Isse, Kumiko
Robson, Simon C.
Geller, David A.
Thomson, Angus W.
CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection
author_facet Yoshida, Osamu
Dou, Lei
Kimura, Shoko
Yokota, Shinichiro
Isse, Kumiko
Robson, Simon C.
Geller, David A.
Thomson, Angus W.
author_sort Yoshida, Osamu
title CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection
title_short CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection
title_full CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection
title_fullStr CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection
title_full_unstemmed CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection
title_sort cd39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection
description Adenosine triphosphate (ATP), an essential metabolic energy source, is released following cell apoptosis or necrosis. It acts as a damage-associated molecule pattern to stimulate innate immune cells. The ectonucleotidase CD39 regulates immune activation by hydrolysis of extracellular ATP. We have shown previously that CD39 expression by donor livers helps protect syngeneic grafts with extended (24 hr) cold preservation time from ischemia reperfusion injury. Given its immune regulatory properties, we hypothesized that CD39 expression in donor livers might modulate transplant tolerance that occurs following mouse allogeneic liver transplantation (LTx). Livers from C57BL/6 (B6) wild-type (WT) or CD39 KO mice were transplanted into normal C3H recipients with minimal (approximately 1 hr) cold ischemia. Serum alanine aminotransferase levels at day 4 post LTx were significantly higher in animals given CD39KO compared with WT livers. Moreover, IFN-γ production by liver-infiltrating CD8+ T cells at day 4 was significantly higher in CD39KO than in WT grafts. Furthermore, splenic T cells from CD39KO liver recipients exhibited greater proliferative responses to donor alloantigens than those from mice given WT grafts. By contrast, there was a concomitant significant reduction in the frequency of regulatory T cells (Treg) in CD39KO than in WT livers. Whereas WT liver allografts survived > 100 days, no CD39KO grafts survived beyond 40 days (median survival time [MST]: WT: >100 days vs CD39KO: 8 days; p<0.01). In addition, soluble CD39 administration significantly prolonged CD39KO liver allograft survival (MST: 27.5 days). These novel data suggest that CD39 expression in liver allografts modulates tissue injury, inflammation, anti-donor effector T cell responses and Treg infiltration and can suppress transplant rejection.
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368493/
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