The role of B cells in the pathogenesis of graft-versus-host disease

Abstract

IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is an established, potentially curative treatment modality for malignant and nonmalignant hematologic diseases. Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic HSCT and limits its wider use. Traditionally, GVHD has been divided into 2 forms, acute and chronic, based on the time of its onset. Acute GVHD has been defined as disease occurring in the first 100 days after transplantation, whereas chronic GVHD occurs after day 100. This arbitrary distinction based on the time of onset fails to reflect the different pathophysiologic mechanisms and clinical manifestations of acute and chronic GVHD, however. Acute GVHD can occur after day 100 in patients who received a nonmyeloablative conditioning regimen or donor lymphocyte infusions. In addition, GVHD with typical clinical features of chronic GVHD can develop well before day 100 and concurrent with acute GVHD. Therefore, the National Institutes of Health consensus development project has defined new criteria for the diagnosis, staging, and response assessment of chronic GVHD. 1,2 Only a few effective therapies are currently available for the treatment of both forms of GVHD. The established immunosuppressive agents are mostly nonspecific and unfortunately associated with severe side effects, in particular the susceptibility to lifethreatening infections. Therefore, novel more selective agents are urgently needed.GVHD is an immune-mediated disease that results from a complex interaction between donor and recipient adaptive immunity. Donor-derived CD4 ϩ and CD8 ϩ T lymphocytes have classically been considered to be the main effector cells mediating GVHD pathogenesis. In fact, removal of T cells from transplant inocula almost completely prevents GVHD from developing, however, at the price of increased incidences of graft rejection and disease recurrence. In recent years, basic and clinical research has provided a more detailed mechanistic understanding of the molecules and cell types involved in the biology of the graft-versushost reaction.Because acute GVHD is thought to be mediated mainly by donor T cells, preventive and therapeutic treatment strategies have focused primarily on the inhibition of T-cell function. Recent animal studies suggest that B cells might also play an important role in the biology of GVHD. Further circumstantial evidence for the involvement of B cells in GVHD pathogenesis comes from reports of successful treatment of GVHD with B-cell depletion. The mechanisms by which B cells contribute to acute and chronic GVHD currently are only incompletely understood. Here, we provide an overview of the experimental and clinical evidence for a pathogenic role of B cells in GVHD and evaluate the implications with regard to B cell-targeted therapies for the treatment of GVHD. We conclude by providing an outlook on novel B cell-specific approaches that might prove beneficial for the treatment of GVHD. B-cell functions in health and diseaseB cells ar...

Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

“…8,9 Clinical manifestations of cGVHD are similar to those observed in connective tissue disease, including scleroderma and sicca syndrome, and autoreactive/alloreactive immune abnormalities have so far been proposed to play a pathogenic role in cGVHD. 10,11 B-cell activating factor has been associated with active cGVHD. 12 The fibrotic change in cGVHD, especially extensive cGVHD, was also associated with the production of autoantibodies against platelet-derived growth factor receptor.…”

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

“…In cGVHD, B cells are essentially recognized as positive regulators of inflammation. 1,8,9 Increased B-cell receptor responsiveness was found in cGVHD patients. 10 B-cell homeostatic defects were described in cGVHD, including elevated B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF)/B-cell ratios, [11][12][13][14][15] expansion of CD21 lo B cells, 16 reduced CD5 1 B1-like cell numbers, 17 decreased CD27 1 memory B cells, and hypogammaglobulinemia.…”

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen

“…GVHD (for the production of autoantibodies from autoreactive B cells) (13). Rituximab (R) has been introduced during 38 conditioning regimen in very few trials, however the results on disease control and prevention of acute or chronic…”