High serum level of a proliferation-inducing ligand (APRIL) is related to increased risk of acute graft-versus host disease in sibling donor hematopoietic stem cell transplantation

Abstract

Introduction: Graft-versus-host disease(GVHD) is one of the major causes of death after allogeneic stem cell transplantation. Traditionally T cells were recognized as the main effector of acute graft-versus-host disease. Many studies reported on the association between GVHD and grafted T cell doses or differentiation of specific T cell subsets. Recently, the role of B cell in the pathogenesis of acute GVHD is under active investigation. B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) are well known cytokines which act in B cell activation, proliferation and differentiation. There are a few evidences that BAFF may have a role in the development of GVHD, The aim of the study is to investigate on serum level of APRIL at early transplantation period for the relationship between APRIL and risk of acute GVHD.Materials and Methods: Forty-five patients who received HLA-matched sibling allogeneic stem cell transplantation in Severance Hospital, Seoul, Korea from September 2003 to September 2009 with remaining stored blood samples were selected. The patients’ serum samples were collected at d+0 and d+14 of transplantation. The APRIL levels in serum samples were measured by commercial ELISA. The grading of acute GVHD was recorded according to Glucksberg severity index.Result: The age at transplantation ranged from 16 to 52 years (median 35.5 yrs). Bone marrow was used in 7 patients (15.6%) and PB in 38 (84.4%). Myeloablative conditioning regimen was used in 17 patients (37.8%) and total body irradiation was applied in 6 patients (13.0%), 28 patients used reduced intensity conditioning regimens. Disease status at transplantation was CR or standard status in 32 patients (71.1%), advanced status in 13 (28.9%). Incidence of all grade of acute GVHD was 55.6% and the incidence of aGVHD exceeding grade 1 was 33.3%. Serum APRIL concentration ranged from 1.859 to 6.219 ng/mL (median 3.101 ng/mL) for d+0 sera and 1.822 to 15.507 ng/mL (median 3.683 ng/mL) for d+14 sera. Patients with higher level of APRIL than median showed correlation with increased tendency of acute GVHD by χ2 test in both d+0 (P=0.021) and d+14 (P=0.147). And then, patients were divided into two groups, the higher group was defined as patients who maintained higher level than median in both d+0 and d+14 (higher group), while the lower group consisted of the patients who had lower level than median in both d+0 and d+14, and alternating group as the others. By χ2 test, the higher group showed statistically significant higher incidence of of acute GVHD compared to the lower group (35.7% vs. 75%, P=0.030). In univariate analysis for clinical risk factors, donor-patient sex mismatch only had statistical relationship with aGVHD. In multivariate analysis, steady higher APRIL level in d+0 and d+14 was the most meaningful variable for increased risk of acute GVHD (Hazard ratio 6.292, P=0.035). Conclusion: This investigation suggests that high serum APRIL concentration at early phase of transplantation can be used as predictor of aGVHD in HLA-matched sibling donor setting. This hypothesis needs to be validated in larger data including alternative donors and various type of transplant settings.