Cytokine Pattern During Rejection and Infection After Liver Transplantation-Improvements in Postoperative Monitoring?

Abstract

Despite improvements in immunosuppression, rejection occurs in 50% of liver transplant patients and may cause significant morbidity. The most frequent cause of death after liver transplantation is severe infection. Determination of the cytokine network may lead to earlier detection of patients at risk for severe rejection and infection. For this purpose, 81 patients with 85 liver transplants were monitored for cytokines and neopterin on a daily basis. During the first postoperative month, 28 patients (34.6%) developed acute rejection; 14 patients were successfully treated with methylprednisolone (steroid-sensitive rejection), while 14 patients required additional treatment with FK506 and OKT3 (steroid-resistant rejection). Ten patients developed severe infections, and 11 patients experienced asymptomatic cholangitis. Patients with an uneventful postoperative course (n=37) were the control group. One-year patient survival was 88.9%: 1 patient died because of chronic rejection and Pseudomonas urosepsis; a further 4 patients died of aspergillus pneumonia and bacterial sepsis. Soluble TNF-RII, sIL-2R-, and IL-10 levels were significantly elevated 3 days prior to or at the onset of acute steroid-resistant rejection (P < or = 0.01 versus steroid-sensitive rejection and on uneventful postoperative course). An increase in IL-8, neopterin, and sTNF-RII was indicative of severe infection 3 days prior to onset of infection. In this group of patients, a simultaneous increase in IL-10 indicated a lethal outcome of severe infection. During the second week of acute steroid-resistant rejection and lethal infection, a significant rise in IL-1beta, IFN-gamma, and IL-6 was observed (P < or = 0.01 versus control groups). The different patterns in neopterin- and cytokine-increase could differentiate between severe rejection and severe infection. Furthermore, the increase in these parameters indicated severe rejection--i.e., steroid resistance at the onset of acute rejection--which could prompt us to initiate rescue therapy immediately. The ability to detect patients at risk for severe or lethal infection may result in intensified infectious screening and more aggressive antiinfectious treatment. Therefore, routine monitoring of these parameters may lead to changes in therapeutic management of severe acute rejection and infection after liver transplantation.

Neopterin: a review

“…Measurement of neopterin levels is a useful early indicator of complications in allograft recipients. In patients who received allografts of tissue such as kidney, liver, pancreas and heart, immunological rejections are indicated by increasing neopterin levels in urine (45) or serum (46)(47)(48), earlier (mean 2 days) than using conventional diagnostic procedures. Similar changes in neopterin levels occur in patients after bone marrow transplantation (49).…”

Cytokine gene polymorphisms and acute human liver graft rejection

“…Such T helper subtype 1 (T H 1)-type proinflammatory cytokines as interleukin-2 (IL-2), IL-15, interferon-␥ (IFN-␥), and tumor necrosis factor-␣ (TNF-␣) are associated mainly with graft rejection, whereas such T H 2-type cytokines as IL-4 have been associated with graft acceptance. [5][6][7][8][9][10][11][12] Also, the T H 2-type cytokine IL-10 has been associated with graft tolerance, 13 although some studies have shown an effect in rejection [14][15][16] and others have shown no association. 6,17 Expression of the T H 2-type cytokine IL-6 may be upregulated, 18,19 downregulated, 6 or unchanged 20 with respect to graft rejection.…”

Relationship between cytokine gene polymorphisms and acute rejection following liver transplantation

“…This study investigated whether a genetic predisposition involving polymorphisms of TH1-, TH2-, or regulatory-type cytokine genes was associated with rejection following human liver transplantation. Several polymorphisms in cytokine genes have been investigated for their possible relationship with cytokine production (Platz et al, 1996;Warlé et al, 2002;Shi et al, 2008;Liu et al, 2009;Zhang and Sun, 2010;Rattanasiri et al, 2013) and graft rejection. Polymorphisms of IL10, TNF, and TGFB1 have been reported to be closely linked to AR (Bathgate et al, 2000;Jonsson et al, 2001;Mas et al, 2004;Azarpira et al, 2013).…”

“…T helper subtype 1 (TH1)-type proinflammatory cytokines, such as interleukin-2 (IL-2), interferon-g (IFN-g), and tumor necrosis factor-a (TNF-a), are associated with graft rejection, whereas TH2-type cytokines such as IL-10 have been associated with graft tolerance (Platz et al, 1996;Shi et al, 2008;Zhang and Sun, 2010). Although some studies have shown an effect on rejection (Warlé et al, 2002;Rattanasiri et al, 2013), others have shown no association (Conti et al, 1998;Xie et al, 2008).…”