Elevated pretransplantation soluble BAFF is associated with an increased risk of acute antibody-mediated rejection.

There is increasing interest in B cells in transplantation, with studies indicating a role in acute and chronic antibody-mediated rejection (AMR) and transplant tolerance (1–3). B-cell activating factor belonging to the tumor necrosis factor family (BAFF; also known as BLyS, TALL-1, and THANK) is a cytokine that enhances B-cell survival and proliferation (4). It exists in both a membrane-bound form and as a soluble trimer and is produced by monocytes, macrophages, dendritic cells (DCs), and, to a lesser extent, T cells (4, 5). There are three BAFF receptors: BAFF-R (also known as BR3), TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), and BCMA (B-cell maturation antigen) (4). These are principally expressed on cells of the B-cell lineage, including plasma cells (6). In addition, BAFF-R is expressed on some activated and regulatory T cells (6, 7). The cytokine APRIL (a proliferation-inducing ligand) also uses TACI and BCMA. The importance of BAFF in B-cell biology and B-cell–mediated autoimmune diseases has been demonstrated by studies in humans and mice. Transgenic mice that overexpress BAFF have increased B-cell survival, hypergammaglobulinemia, and pathogenic autoantibodies (which arise independently of T-cell help) and spontaneously develop a lupus-like autoimmune disease (8). Furthermore, elevated serum BAFF levels have been described in patients with autoantibody-associated autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjogren’s syndrome, and idiopathic thrombocytopenic purpura (9–11). Studies of BAFF in the context of solid-organ transplantation are less frequent; in a murine cardiac allograft model, BAFF-deficient recipients had extended transplant survival, particularly if a calcineurin inhibitor was administered (7). The deleterious effect of BAFF on allograft survival in this model was dependent on BAFF-R and independent of TACI and BCMA. In a murine islet allograft model, BAFF blockade with a monoclonal antibody (in combination with rapamycin at induction) resulted in long-term survival of major histocompatibility complex–disparate islet allografts (12). In humans, BAFF has been identified by immunohistochemistry in renal transplant biopsies with acute rejection and appeared to correlate with C4d deposition (13). In a small study of long-term renal allograft recipients, the presence of BAFF-positive CD4 T cells in peripheral blood was associated with worse transplant function (14) and elevated BAFF mRNA and protein have been noted in kidneys explanted for chronic rejection, with infiltrating mononuclear cells the principle source (15). BAFF-R–positive B and T cells have also been identified in human renal allografts with chronic rejection (7). More recently, Thibault-Espitia et al. reported that patients undergoing antibody-compatible (Ac) transplantation with higher circulating soluble BAFF had a significantly greater risk of developing donor-specific antibodies (DSA) and that, in patients with stable graft function, high BAFF-R mRNA in peripheral blood mononuclear cells was associated with the development of graft dysfunction (16). Given the importance of BAFF in B-cell biology and the increasing evidence (outlined above) indicating a role in renal transplantation, we set out to assess serum BAFF levels in patients with end-stage renal failure undergoing renal transplantation and to determine if serum BAFF levels might predict risk of AMR. Here, we demonstrate that, in patients undergoing antibody-incompatible (Ai) renal transplantation, elevated serum BAFF levels at baseline (before both antibody removal/desensitization and transplantation) are associated with a heightened risk of subsequent AMR. Lower BAFF levels did not allow risk stratification. In Ac transplant recipients at lower risk of AMR, the rate of AMR in patients with the highest pretransplantation soluble BAFF was not statistically significantly different from those with lower BAFF levels. These data raise the possibility that, in patients undergoing Ai transplantation, elevated BAFF levels might allow the identification of those at greatest risk of AMR. Given the known roles of BAFF in B-cell biology and the availability of BAFF-blocking agents (17), BAFF neutralization in these individuals may be an interesting therapeutic strategy to explore and might help to determine whether BAFF plays a causative role in rejection.