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

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

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Title: CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection
Author: Yoshida, Osamu; Dou, Lei; Kimura, Shoko; Yokota, Shinichiro; Isse, Kumiko; Robson, Simon C.; Geller, David A.; Thomson, Angus W.

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Citation: Yoshida, Osamu, Lei Dou, Shoko Kimura, Shinichiro Yokota, Kumiko Isse, Simon C. Robson, David A. Geller, and Angus W. Thomson. 2015. “CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection.” Transplant immunology 32 (2): 76-83. doi:10.1016/j.trim.2015.01.003. http://dx.doi.org/10.1016/j.trim.2015.01.003.
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Abstract: 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.
Published Version: doi:10.1016/j.trim.2015.01.003
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368493/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:26318620
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