B cells in GVHD: friend or foe?

To the editor:

We were pleased to read the recent review by Shimabukuro-Vornhagen et al, “The role of B cells in the pathogenesis of graft-versus-host disease,” which highlights the importance of B cells after bone marrow transplantation, as B cells have tended to be overlooked as a contributor to transplantation immunology.¹  This review comprehensively describes the use of the humanized chimeric CD20 monoclonal antibody, rituximab, for the prophylaxis and treatment of acute and steroid-refractory chronic graft-versus-host disease (GVHD).¹  Three key observations have been made: (1) the use of rituximab as part of pretransplantation conditioning results in the in vivo depletion of donor B cells after transplantation; (2) pretransplantation rituximab is associated with reduced incidence and severity of acute GVHD in a cohort of patients; and (3) elevated B-cell numbers in donor grafts are associated with the development of both acute and chronic GVHD. Whether B-cell depletion per se is the mechanism underlying reduced GVHD rates, and whether this reflects a direct role of B cells in stimulating allogeneic T-cell expansion and effector function remains unknown.

It is important to also consider the potential nonspecific effects of rituximab therapy on the activation of allogeneic T cells. Nonspecific IgG treatment, such as high-dose intravenous immune globulin, can inhibit interferon-γ (IFN-γ) responses in macrophages via a FcγRIII-dependent mechanism, and induce natural killer cell–mediated antibody-dependent cellular cytotoxicity of dendritic cells (DCs).^2,3  Apoptotic lymphocytes also have a regulatory effect upon DCs, by down-regulating costimulatory molecules and inducing the production of the immunosuppressive cytokine interleukin-10 (IL-10).^4,5  In GVHD, these events stimulate the generation and proliferation of regulatory T cells (Tregs), thus suppressing allogeneic T-cell activation.

Both T and B lymphocytes play a role in tolerance induction to autoantigens, whereby CD4⁺ T cells regulate early allogeneic T-cell activation and expansion, and B cells control their differentiation into effector T cells.⁶  Host B cells have also been shown to play a protective role in GVHD, via the secretion of IL-10 after total body irradiation, thus inhibiting alloreactive T-cell expansion and subsequent acute GVHD induction.⁷  Donor B cells can also inhibit acute GVHD in a major histocompatibility complex class II– and Treg-dependent manner. Mice receiving BM from B cell–deficient mutant mice (B6.μMT) developed rapid-onset acute GVHD, contributed by faster donor CD8⁺ T-cell engraftment and production of IL-2 and IFN-γ (J.E.D., V. Watt, and D.R.S., manuscript in preparation), and indirect alloantigen presentation to CD4⁺ T cells.⁸  This is supported by recent in vitro human data, indicating that activated B cells directly suppress allogeneic CD4⁺ T-cell proliferation through the expansion of alloantigen-specific suppressor Tregs.⁹ 

While clinical observations indicate that rituximab has a beneficial effect in the prophylaxis of acute GVHD, it is worth considering that an alternate mechanism of its action may exist over and above simple B-cell depletion. Furthermore, the potential benefit of regulatory B cells may be lost if rituximab is adopted wholesale into pretransplantation conditioning regimens.