Liver grafts from CD39‐overexpressing rodents are protected from ischemia reperfusion injury due to reduced numbers of resident CD4+ T cells

• Published in: Hepatology (Baltimore, Md.) Vol. 57; no. 4; pp. 1597 - 1606
• Main Authors: Pommey, Sandra, Lu, Bo, McRae, Jennifer, Stagg, John, Hill, Prue, Salvaris, Evelyn, Robson, Simon C., d'Apice, Anthony J.F., Cowan, Peter J., Dwyer, Karen M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2013; Wiley Subscription Services, Inc
• Subjects: Alanine Transaminase - blood; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Apyrase - genetics; Apyrase - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Cold; Disease Models, Animal; Hepatology; Interleukin-6 - blood; Ischemia; Killer Cells, Natural - pathology; Liver; Liver Transplantation - immunology; Liver Transplantation - pathology; Lymphocytes; Lymphopenia - genetics; Lymphopenia - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Rodents; T-Lymphocytes, Regulatory - pathology; Transplants & implants; Up-Regulation
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.25985

Ischemia‐reperfusion injury (IRI) is a major limiting event for successful liver transplantation, and CD4+ T cells and invariant natural killer T (iNKT) cells have been implicated in promoting IRI. We hypothesized that hepatic overexpression of CD39, an ectonucleotidase with antiinflammatory functions, will protect liver grafts after prolonged cold ischemia. CD39‐transgenic (CD39tg) and wildtype (WT) mouse livers were transplanted into WT recipients after 18 hours cold storage and pathological analysis was performed 6 hours after transplantation. Serum levels of alanine aminotransferase and interleukin (IL)‐6 were significantly reduced in recipients of CD39tg livers compared to recipients of WT livers. Furthermore, less severe histopathological injury was demonstrated in the CD39tg grafts. Immune analysis revealed that CD4+ T cells and iNKT cells were significantly decreased in number in the livers of untreated CD39tg mice. This was associated with a peripheral CD4+ T cell lymphopenia due to defective thymocyte maturation. To assess the relative importance of liver‐resident CD4+ T cells and iNKT cells in mediating liver injury following extended cold preservation and transplantation, WT mice depleted of CD4+ T cells or mice genetically deficient in iNKT cells were used as donors. The absence of CD4+ T cells, but not iNKT cells, protected liver grafts from early IRI. Conclusion: Hepatic CD4+ T cells, but not iNKT cells, play a critical role in early IRI following extended cold preservation in a liver transplant model. (HEPATOLOGY 2013)