Recipient B Cells Are Not Required for Graft-Versus-Host Disease Induction

Abstract

Recipient antigen presenting cells (APCs) are required for CD8-mediated GVHD and have an important and nonredundant role in CD4-mediated GVHD in mouse MHC-matched allogeneic bone marrow transplantation (alloBMT). However, the precise roles of specific recipient APCs — dendritic cells, macrophages, and B cells — are not well defined. If recipient B cells are important APCs they could be depleted with Rituximab, an anti-CD20 monoclonal antibody. On the other hand, B cells can downregulate T cell responses and consequently B cell depletion could exacerbate GVHD. Patients with B cell lymphomas undergo allogeneic hematopoietic stem cell transplantation (alloSCT) and many are B-cell-deficient due to prior Rituximab. We therefore studied the role of recipient B cells in MHC-matched murine models of CD8- and CD4-mediated GVHD by using recipients genetically deficient in B cells and with antibody-mediated depletion of host B cells. In both CD4-and CD8-dependent models, B cell deficient recipients developed clinical and pathologic GVHD. However, although CD8-mediated GVHD was clinically less severe in hosts genetically deficient in B cells, it was unaffected in anti-CD20-treated recipients. These data indicate that recipient B cells are not important initiators of GVHD and that efforts to prevent GVHD by APC depletion should focus on other APC subsets.

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

“…Although a previous study indicated that host B cells suppress GVHD, 8 CD19 expression in recipients did not alter the course or severity of Scl-cGVHD (Figure 2). This study demonstrates, for the first time, that Bregs play a critical suppressive role in immune-mediated fibrotic diseases.…”

“…Donor T cells have classically been considered the main effector cells, although recent studies have suggested that B cells also play fundamental roles in GVHD. [5][6][7][8] Circulating autoantibodies are frequently detected in cGVHD patients. 9 Their direct pathogenicity remains unclear, although a recent study has demonstrated that pathogenic antibody production from germinal centers plays a causal role in development of cGVHD.…”

Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

“…Because host hematopoietic-derived APCs can also negatively regulate GVH responses, 37,38 our data indicate that strategies that promote the regulatory APC subsets [39][40][41][42] might be more effective than elimination of hematopoietic-derived activating APC subsets. 28,[43][44][45] Importantly, our data indicate that regulating the process of Ag presentation, rather than targeting any specific host hematopoietic-derived cellular subsets that are capable of activating alloreactive donor T cells, might be a more desirable strategy for mitigating GVHD. …”

Profound Depletion of Host Conventional Dendritic Cells, Plasmacytoid Dendritic Cells, and B Cells Does Not Prevent Graft-versus-Host Disease Induction

“…The BST2 hybridoma(27) was a gift from Marco Colonna (Washington University School of Medicine, MO) and was lab-prepared. Anti-mouse CD20 (an IgG2aκ derivative of clone 18B12(28)) was provided by Marilyn Kehry (Biogen/IDEC, San Diego, CA).…”