Patients without chronic graft-versus-host disease (cGVHD) have robust B cell reconstitution and are able to maintain B cell homeostasis after allogeneic hematopoietic stem cell transplantation (HSCT). To determine whether B lymphopoiesis differs before cGVHD develops, we examined bone marrow (BM) biopsies for terminal deoxynucleotidyl transferase (TdT) and PAX5 immunostaining early post-HSCT at day 30 when all patients have been shown to have high B cell activating factor (BAFF) levels. We found significantly greater numbers of BM B cell precursors in patients who did not develop cGVHD compared with those who developed cGVHD (median = 44 vs 2 cells/high powered field [hpf]; respectively; P < .001). Importantly, a significant increase in precursor B cells was maintained when patients receiving high-dose steroid therapy were excluded (median = 49 vs 20 cells/hpf; P = .017). Thus, we demonstrate the association of BM B cell production capacity in human GVHD development. Increased BM precursor B cell number may serve to predict good clinical outcome after HSCT.
[Show abstract][Hide abstract] ABSTRACT: Recent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD). Patients with cGVHD have delayed B-cell reconstitution and elevated BAFF to B-cell ratios compared to patients without cGVHD. The mechanisms promoting and sustaining B-cell activation in this disease, however, remain unknown. As BAFF increases murine B-cell metabolism and survival and maintains autoreactive B-cell clones, we performed ex vivo analyses of peripheral B cells from 51 patients who either had or did not have active cGVHD and were greater than 1 year from the time of allogeneic hematopoietic stem cell transplantation. We found that B cells from patients with active cGVHD were in a heightened metabolic state and were resistant to apoptosis. Exogenous BAFF treatment amplified cell size and survival in B cells from these patients. We found significantly increased signaling through ERK and AKT that associated with decreased levels of proapoptotic Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell survival. Thus, we identify a role for BAFF in the pathogenesis of cGVHD and define B-cell activation and survival pathways suitable for novel therapeutic development in cGVHD.
[Show abstract][Hide abstract] ABSTRACT: B cells are implicated in the pathophysiology of chronic GVHD and phase II trials suggest that B cell depletion can treat established chronic GVHD. We hypothesized that post-transplantation B cell depletion could prevent the occurrence of chronic GVHD. We performed a 65 patient phase II trial of rituximab (375 mg/m(2) iv), administered at 3, 6, 9 and 12 months after transplantation. Rituximab administration was safe without severe infusional adverse events. The cumulative incidences of chronic GVHD and systemic corticosteroid-requiring chronic GVHD at 2 years from transplantation were 48% and 31% respectively, both lower than the corresponding rates in a concurrent control cohort (60%, p=0.1 and 48.5%, p=0.015). There was no difference in relapse incidence, but treatment-related mortality at 4 years from transplantation was significantly lower in treated subjects when compared with controls (5% vs. 19%, p=0.02) and overall survival was superior at 4 years (71% vs. 56%, p=0.05). At 2 years from transplantation, the BAFF/B cell ratio was significantly higher in subjects who developed chronic GVHD in comparison with those without chronic GVHD (p=0.039). Rituximab can prevent systemic corticosteroid-requiring chronic GVHD after peripheral blood stem cell transplantation and should be tested in a prospective randomized trial. Trial registered at www.clinicaltrials.gov (NCT00379587).
[Show abstract][Hide abstract] ABSTRACT: Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution ("BM GVHD"). In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P = 0.0427, vs. patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P = 0.012) and flow cytometric analyses revealed lower numbers of CD19+ B cells and significantly increased CD4/CD8 ratio (P = 0.0002) in these patients. Our data for the first time summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; 20(4). DOI:10.1016/j.bbmt.2013.12.568 · 3.40 Impact Factor
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