Background: ATP is an energy source stored in the cell cytosol. Once released into extracellular(e) space as a result of cell injury/death, eATP acts in a comparable manner to DAMPs (damage-associated molecule pattern) and is able to activate immune cells. CD39 hydrolyzes eATP and maintains purinergic homeostasis. It is expressed on Treg and eATP hydrolysis by CD39 is recognized as an immune regulatory function of these cells. We have found that conventional mouse liver myeloid(m) DC express comparatively high levels of surface CD39 and that this contributes to ATP hydrolysis and hypo responsiveness to ATP, when compared with secondary lymphoid tissue DC. We hypothesized that CD39 might confer protection against the activation/immune stimulatory function on liver DC and reduce liver transplant ischemic-reperfusion injury (IRI).
METHODS: Liver mDC were isolated by immunomagnetic sorting from C57BL/6 WT or CD39KO mice treated with the endogenous DC poietin Flt3 ligand. Expression of MHCII and costimulatory molecules (CD40, CD80 and CD86), inflammatory cytokines (IL-6, IL-12p40, TNF-Α and MCP-1) production and T cell stimulatory and Treg-inducting ability were compared between WT and CD39KO liver DC. For cold IRI, syngeneic orthotropic liver transplantation was conducted with 18hr cold preservation of WT/CD39KO donor livers. Liver injury was evaluated 6hr after transplantation by serum ALT and quantitative histological analysis. Graft DC phenotype was analyzed by flow cytometry. Expression of inflammatory cytokines in grafts was measured by RT-PCR.
RESULTS: Compared with WT liver DC, CD39KO liver DC expressed higher levels of MHCII and costimulatory molecules with/without TLR4 ligation, produced higher levels of inflammatory cytokines, and exhibited stronger allogeneic T cell stimulatory capacity and less Treg-inducing ability. Mice given CD39KO livers showed more severe liver injury than those given WT grafts. DC in CD39KO grafts expressed higher levels of MHCII and costimulatory molecules. Inflammatory cytokines were expressed at higher levels in CD39KO, when compared with WT liver grafts.
CONCLUSION: CD39 expression regulates the activation and immunostimulatory function of conventional liver DC and offers protective effects in liver transplant IRI.
To cite this abstract in AMA style:Yoshida O, Kimura S, Robson S, Murase N, Thomson A. CD39 Regulates the Activation of Liver DC and Protects Against Liver Transplant Ischemic Reperfusion Injury [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/cd39-regulates-the-activation-of-liver-dc-and-protects-against-liver-transplant-ischemic-reperfusion-injury/. Accessed January 17, 2021.
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