Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease

Abstract

AbstractChronic graft-versus-host disease (cGVHD) is an increasingly frequent cause of morbidity and mortality of allogeneic hematopoietic stem-cell transplantation. Sclerodermatous cGVHD (Scl-cGVHD) is characterized by fibrosis and autoimmune features resembling those of systemic sclerosis (SSc). Transplantation of B10.D2 bone marrow and splenocytes into irradiated BALB/c mice is an established model of human Scl-cGVHD. To examine the role of B cells in Scl-cGVHD, CD19-deficient (CD19−/−) mice were used as donors or recipients. CD19−/− donors induced more severe Scl-cGVHD than wild-type donors, but use of CD19−/− recipients resulted in no significant differences compared with wild-type recipients. Moreover, CD19 deficiency on donor B cells resulted in the expansion of splenic interleukin (IL) -6–producing monocytes/macrophages, cytotoxic CD8+ T cells, and Th1 cells during the early stage of disease and increased the infiltration of T cells, TGF-β–producing monocytes/macrophages, and Th2 cells into the skin in the later stage of Scl-cGVHD. IL-10–producing regulatory B cells (B10 cells) were not reconstituted by CD19−/− donor cells, and early adoptive transfer of B10 cells attenuated the augmented manifestations of CD19−/− donor-induced Scl-cGVHD. Therefore, donor-derived B10 cells have a suppressive role in Scl-cGVHD development, warranting future investigation of regulatory B-cell–based therapy for treatment of Scl-cGVHD and SSc.