title: 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.
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, California; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope National Medical Center, Duarte, California.
authors.forename: Heather F
authors.initials: HF
authors.lastname: Johnston
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, California; Department of Hematology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, California; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope National Medical Center, Duarte, California.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Racine
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, California; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope National Medical Center, Duarte, California.
authors.forename: Kaniel
authors.initials: K
authors.lastname: Cassady
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, California; Department of Hematology, Changhai Hospital, The Second Military Medical School, Shanghai, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Ni
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, California; Department of Hematology, Changhai Hospital, The Second Military Medical School, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Research Biology, Genentech, San Francisco, California.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, California; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope National Medical Center, Duarte, California.
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, California; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope National Medical Center, Duarte, California. Electronic address: dzeng@coh.org.
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D061067:Antibodies, Monoclonal, Humanized
keywords: Acute GVHD; Anti-CD20; B cell depletion; Chronic GVHD; GVHD; Therapy