Value of Soluble CD30 in Liver Transplantation E. Fábrega, M.G. Unzueta, M. Cobo, F. Casafont, J.A. Amado, and F.P. Romero ABSTRACT Introduction. CD30 is a membrane glycoprotein that belongs to the tumor necrosis factor superfamily. It is expressed on activated T cells. After activation of CD30⫹ T cells, a soluble form of CD30 (sCD30) released into the bloodstream, can be measured in the serum. The aim of our study was to investigate the time course of serum levels of sCD30 during hepatic allograft rejection. Materials and methods. Serum levels of sCD30 were determined in 30 healthy subjects and 50 hepatic transplant recipients. These patients were divided into two groups: group I, 35 patients without rejection; and group II, 15 patients with acute rejection. Samples were collected on day 1 and 7 after transplantation and on the day of liver biopsy. Results. The concentrations of sCD30 were similar in the rejection (40.4 ⫾ 16.5 U/mL) and nonrejection groups (43.0 ⫾ 18.2 U/mL) on postoperative day 1. We observed a significant increase in sCD30 levels in the rejection group on postoperative day 7 (76.3 ⫾ 61.8 U/mL vs 46.8 ⫾ 20.5 U/mL; P ⫽ .01). The difference increased when a diagnosis of acute rejection had been established: namely 133.0 ⫾ 113.5 U/mL versus 40.1 ⫾ 22.0 U/mL; (P ⫽ .001). These levels were also significantly higher during the entire postoperative period in all the patients, with or without rejection, than those observed in healthy controls (26.6 ⫾ 5.3 U/mL; P ⫽ .005). Conclusions. The release of circulating sCD30 is a prominent feature coinciding with the first episode of hepatic allograft rejection. So, monitoring of sCD30 levels may be useful for the early diagnosis of an acute rejection episode.
ESPITE PROGRESS in the field of immunosuppressive therapeutics, acute rejection episodes (AREs) are still a common complication in about 30% of liver transplantations (OLTs). CD30 is a 120-kDa transmembrane glycoprotein that belongs to the tumor necrosis factor and nerve growth factor receptor superfamily.1 It is expressed on CD4⫹ and CD8⫹ activated T cells that secrete Th2-type cytokines. After activation of CD30⫹ T cells, a soluble form of CD30 (sCD30) is released into the blood stream, leading to the speculation that sCD30 levels may be closely related to CD30 expression on T cells and therefore serve as a marker for immune activation.2 Although the role of CD30 in allograft rejection is still unknown, increased pretransplantation and posttransplantation concentrations of sCD30 have been associated with an increased incidence of acute as well as chronic renal allograft rejection.3,4 The aim of the present study was to investigate the kinetics of serum levels of sCD30 during hepatic allograft rejection.
PATIENTS AND METHODS We analyzed 50 liver transplant recipients who were divided according to the occurrence of ARE: Yes (n ⫽ 15) vs no (nonARE; n ⫽ 35). A clinical diagnosis of ARE was considered when transaminases values or bilirubin levels rose without evidence of other causes of allograft dysfunction, such as infection or thrombosis; it was confirmed by pathological evidence in all cases. Blood samples for sCD30 measurements were collected at 1, 7, and 15 days after OLT in the non-ARE group. In the rejection group, the From the Gastroenterology and Hepatology Unit (E.F., M.C., F.C., F.P.R.) and Endocrinology Unit (M.G.U., J.A.A.), University Hospital “Marqués de Valdecilla,” Faculty of Medicine, Santander, Spain. This work was supported in part by grant FISS PI030330 and RNIGH. Address reprint requests to Emilio Fábrega, MD, Gastroenterology and Hepatology Unit, University Hospital “Marqués de Valdecilla,” Faculty of Medicine, Avenida Valdecilla s/n, Santander 39008, Spain. E-mail: [email protected]
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0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.06.036
Transplantation Proceedings, 39, 2295–2296 (2007)
2296 blood samples were drawn on days 1 and 7 and between days 12 and 18 after OLT (on the day of the liver biopsy). No patient showed pretransplant anti-HLA antibodies. Thirty age-matched healthy subjects were used as normal controls. Serum sCD30 was measured using a commercial enzyme-linked immunoassay (Bender MedSystems, Austria) according to the manufacturer’s instructions. The study was approved by the hospital ethical committe. Data were expressed as mean values ⫾ SEM. MannWhitney U and Kruskal Wallis tests were used for comparisons between patients and controls and within the patient group, respectively. P values ⬍.05 were considered significant.
Levels of sCD30 were significantly higher in all the transplanted patients at any time after transplantation than in healthy controls (26.6 ⫾ 5.3 U/mL; P ⫽ .005). Serum levels of sCD30 were similar in the ARE (40.4 ⫾ 16.5 U/mL) and the non-ARE groups (43.0 ⫾ 18.2 U/mL) on postransplant day 1. We observed a significant increase in sCD30 levels among the rejection group on day 7 (76.3 ⫾ 61.8 U/mL vs 46.8 ⫾ 20.5 U/mL; P ⫽ .01), a difference that increased at the time of rejection diagnosis (133.0 ⫾ 113.5 U/mL vs 40.1 ⫾ 22.0 U/mL; P ⫽ .001). (Fig 1).
FÁBREGA, UNZUETA, COBO ET AL
sCD30 levels represented a risk factor for bronchiolitis obliterans syndrome.6 Thus, these studies suggested that a Th2-type immune response leading to B-cell activation might play a pivotal role in allograft rejection and that Th-2-type cytokines or cell transducers might help to predict the risk of allograft loss.7 In OLT, the role of the humoral response in ARE has been recognized recently.8 In the present study, we demonstrated that increased sCD30 during the early period after OLT is significantly associated with impaired graft function and served as an indicator of graft deterioration due to ARE. Our data were consistent with a previous report in living donor OLT by Kim et al that showed significant differences in sCD30 levels between patients with and without ARE.9 Altogether, these findings support the notion that the humoral immune response, due to Th2 lymphocyte activation and involvement of B-cellrelated mechanisms, may play a greater role in liver ARE than it was previously thought.8,10,11 In conclusion, the release of circulating sCD30 is a prominent feature during an episode of liver allograft rejection. Thus, its monitoring may be useful to identify patients with a immunological risk of ARE in order to tailor immunosuppression.
The exact function of CD30⫹ T cells in the immune response is not fully understood. However, sCD30 levels are elevated in autoimmune conditions with predominant Th2 activation, such as atopic dermatitis.1 Studies on renal transplant recipients provided the first clinical evidence for increased sCD30 levels as significant risk factor for an ARE, for chronic nephropathy, and for decreased graft survival.3,4 Similar observations have been made in heart transplant patients.5 Furthermore, in lung transplant patients increased pretransplantation and posttransplantation
Fig 1. Time course of sCD30 serum levels after liver transplantation. An asterisk indicates a significant difference between rejectors and nonrejectors.
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