Administration of anti-CD20 mAb is highly effective in preventing but ineffective in treating chronic graft-versus-host disease while preserving strong graft-versus-leukemia effects

Abstract

Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome, and donor B cells play important roles in augmenting its pathogenesis. B cell-depleting anti-CD20 mAb has been administered before or after cGVHD onset for preventing or treating cGVHD in the clinic. Although administration before onset appeared to be more effective, the effect is variable and sometimes minimal. Here, we used 2 mouse cGVHD models to evaluate the preventive and therapeutic effect of anti-CD20 mAb. With the model of DBA/2 donor to MHC-matched BALB/c recipient, 1 intravenous injection of anti-CD20 mAb (40 mg/kg) the following day or on day 7 after hematopoietic cell transplantation when serum autoantibodies were undetectable effectively prevented induction of cGVHD and preserved a strong graft-versus-leukemia (GVL) effect. The separation of GVL effect from GVHD was associated with a significant reduction of donor CD4(+) T cell proliferation and expansion and protection of host thymic medullary epithelial cells. Anti-CD20 mAb administration also prevented expansion of donor T cells and induction of cGVHD in another mouse model of C57BL/6 donor to MHC-mismatched BALB/c recipients. In contrast, administration of anti-CD20 mAb after GVHD onset was not able to effectively deplete donor B cells or ameliorate cGVHD in either model. These results indicate that administration of anti-CD20 mAb before signs of cGVHD can prevent induction of autoimmune-like cGVHD while preserving a GVL effect; there is little effect if administered after cGVHD onset. This provides new insights into clinical prevention and therapy of cGVHD with B cell-depleting reagents.

Keywords: Acute GVHD; Anti-CD20; B cell depletion; Chronic GVHD; GVHD; Therapy.