Inflammatory markers sampled by microdialysis catheters distinguish rejection from ischemia in liver grafts

Abstract

Rejection and ischemia are serious complications after liver transplantation. Early detection is mandatory, but specific markers are largely missing, particularly for rejection. The objective of this study was to explore the ability of microdialysis catheters inserted in liver grafts to detect and discriminate rejection and ischemia through postoperative measurements of inflammatory mediators. Microdialysis catheters with a 100-kDa pore size were inserted into 73 transplants after reperfusion. After the study's completion, complement activation product 5a (C5a), C-X-C motif chemokine 8 (CXCL8), CXCL10, interleukin-1 (IL-1) receptor antagonist, IL-6, IL-10, and macrophage inflammatory protein 1b were analyzed en bloc in all grafts with biopsy-confirmed rejection (n ¼ 12), in grafts with vascular occlusion/ischemia (n ¼ 4), and in reference grafts with a normal postoperative course of circulating transaminase and bilirubin levels (n ¼ 17). The inflammatory mediators were elevated immediately after graft reperfusion and decreased toward low, stable values during the first 24 hours in nonischemic grafts. In grafts suffering from rejection, CXCL10 increased significantly (P ¼ 0.008 versus the reference group and P ¼ 0.002 versus the ischemia group) 2 to 5 days before increases in circulating alanine aminotransferase and bilirubin levels. The area under the receiver operating characteristic curve was 0.81. Grafts with ischemia displayed increased levels of C5a (P ¼ 0.002 versus the reference group and P ¼ 0.008 versus the rejection group). The area under the curve was 0.99. IL-6 and CXCL8 increased with both ischemia and rejection. In conclusion, CXCL10 and C5a were found to be selective markers for rejection and ischemia, respectively. Liver Transpl 18:1421-1429, 2012. V C 2012 AASLD.Received March 30, 2012; accepted June 13, 2012.Most rejections of liver transplants are cellular rather than antibody-mediated, and T lymphocytes are central players.1 Acute cellular rejection (ACR) typically occurs within the first 6 weeks after transplantation and is a relatively frequent complication with an incidence in the range of 30% to 60%.2 The detection and subsequent treatment of ACR are important because the condition may have a negative impact on outcomes, particularly for patients undergoing transplantation for hepatitis C cirrhosis and primary sclerosing cholangitis. [2][3][4][5][6][7] ACR is suspected when the activity of circulating transaminases and/or concentrations of Abbreviations: ACR, acute cellular rejection; ALT, alanine transaminase; AST, aspartate transaminase; AUC, area under the curve; C5a, complement activation product 5a; CI, confidence interval; CXCL, C-X-C motif chemokine; IL, interleukin; IL-1ra, interleukin-1 receptor antagonist; MIP, macrophage inflammatory protein; OLT, orthotopic liver transplantation; s-ALT, serum alanine aminotransferase.

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…Early-stage infection IL-10 synthesis can also involve the neutrophils, because inhibition of IL-10 signaling abrogated the increase in Leshmania parasite loads in BALB/c mice during the first week [89]. Apart from acute phase infections, the IL-10 involvement during the first week is observed even in intracellular pathogens, tumors, and transplants, which demonstrate implication of PMCs, NK, and CD4+ T cells in the IL-10 synthesis [130,156,158,165,166]. Increased IL-10 production by CD4CD25FoxP3+ T cells along few weeks was observed in a time-dependent manner during melanoma tumor growth in mice, while the initial association of IL-10 production with migration of macrophages, DCs, and neutrophils following peritoneal scaffold implantation was replaced by association with T lymphocytes that became prevalent by day 14 [124,142].…”

“…Deviation Some studies support the fact that the immune effect that is associated/simultaneously effected with IL-10 production can be developed independently to this cytokine, indicating that IL-10 is required to license regulatory function, but its production is not itself required for development of respective events [132,143,150,158]. In this context, a wide range of cytokines can mediate the rescue tumor growth, as well as the liver and renal transplant rejection independently to (and in presence of) increased Btolerogenic^IL-10 level [120,124,130,132,134,149,156,158].…”

“…In general, the microenvironment of the tolerant allograft can reveal a decrease in pro-inflammatory mediators (IFN-γ, TNF-α) and an increase in the anti-inflammatory mediator IL-10, as well as increased expression of the master regulator of Tregs, FoxP3 [157]. However, the IL-10 increase can be evidenced even during transplant rejection and ischemia in association with a wide range of inflammatory cells and cytokines [158].…”

“…In this context, a wide range of cytokines can mediate the rescue tumor growth, as well as the liver and renal transplant rejection independently to (and in presence of) increased Btolerogenic^IL-10 level [120,124,130,132,134,149,156,158]. This turn-around of immune system action is achieved through mobilization and activation of FoxP3+ Tregs, myeloid-derived suppressor cells, tumor-associated macrophages, and fibroblasts, all of which suppress CD8+ T and NK cells at least in the early stages of Bimmune evasion^ [120,124,134].…”

Systemic CD14 Inhibition Attenuates Organ Inflammation in Porcine Escherichia coli Sepsis

“…We have previously shown that IP-10 was inhibited significantly by anti-CD14 in vitro in whole blood in humans (39) and show here for the first time that the same striking effect is seen in vivo in organs in pigs. IP-10 is also important in sterile inflammation, i.e., the rejection of liver grafts (42,43). Importantly, because of its profound effect on T cells, IP-10 seems to be a link in the inflammatory network between innate and adaptive immunity.…”