Traditionally T cells were recognized as main effector of acute graft-versus-host disease. Many studies revealed that grafted T cell dose and activity or repertoire development of T cell is related to GVHD. Recently, the role of B-cells in pathogenesis of acute GVHD is actively investigated. BAFF and APRIL is known to be related to increased activity of many autoimmune diseases. APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor superfamily secreted by myeloid cells, dendritic cells and T cells. We studied on serum level of APRIL at early transplantation period for investigation of relationship between APRIL concentration and risk of acute GVHD.
Forty-six patients who received HLA-matched sibling allogeneic stem cell transplantation in Severance Hospital From September 2003 to September 2009 with remaining stored blood samples were selected. Blood samples were collected at day 0 and day 14. After clot formation, sera were separated at 1,000 g for 3 minutes then stored at -80°C for analysis. Samples were measured by commercial ELISA kit for APRIL (Bender MedSystems, Vienna, Austria) according to the manufacturer's recommendations. Grading of acute GVHD followed IBMTR severity index.
Age at transplantation ranged from 16 to 52 years(median 35.5 yrs). Bone marrow was used in 7 patients (15.2%) and PB in 39(84.8%). Myeloablative conditioning regimen was used in 18 patients (39.1%) and total body irradiation in 6 patients (13.0%), 28 patients used reduced intensity conditioning regimens. Disease status at SCT was CR 29 patients (63%), non-CR 14(30.4%). Incidence of all grade of acute GVHD was 56.5% (26 patients) and incidence of aGVHD exceeding grade 1 was 34.8% (16 patients). Serum APRIL concentration ranged from 1.859 to 6.219 (median 3.101 ng/mL) for day0 sera and 1.822 to 15.507 (median 3.683 ng/mL) for day14 sera. Patients with higher level than median concentration showed correlation with increased tendency of acute GVHD by χ2 test in both day 0 (P=0.021) and day 14 (P=0.147). And then, patients were divided into two groups, one group included patients with steady higher level than median in both day 0 and day 14 (group1), while the others constituted group2. By χ2 test, group 1 showed correlation with acute GVHD (P=0.037). In multivariate analysis, conditioning intensity, donor-patient sex mismatch, stem cell dose, CD3+ cell dose, donor parity were included with steady higher APRIL level as variables. Higher APRIL was strongest variable for increased risk of acute GVHD (hazard ratio 64.67, P=0.005).
Our data suggest that higher level of APRIL at early phase of allogeneic stem cell transplantation with HLA-matched sibling donor can be used as predictor of acute GVHD. Confirm of our hypothesis should be done also in larger patient data including alternative donors.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.