Abstract
Chronic antibody mediated rejection (cAMR) remains a significant barrier to achieving long-term graft survival in kidney transplantation, which results from alloantibody production from B lymphocytes and plasma cells. APRIL (A proliferation-inducing ligand) and BLyS (B lymphocyte stimulator) are critical survival factors for B lymphocytes and plasma cells. Here we describe the results of APRIL/BLyS blockade in a murine cAMR kidney transplant model. c57/B6 mice underwent kidney transplantation with Bm12 kidneys (minor MHC mismatch), a well-described model for chronic rejection where animals cannot make donor specific antibody but rather make antinuclear antibody (ANA). Following transplantation, animals received TACI-Ig (to block APRIL and BLyS) or no treatment. Animals were continued on treatment until harvest 4 weeks following transplant. Serum was analyzed for circulating anti-nuclear autoantibodies using HEp-2 indirect immunofluorescence. Spleen and transplanted kidneys were analyzed via H&E. ANA production was significantly decreased in APRIL/BLyS blockade treated animals (p<0.0001). No significant difference in autoantibody production was found between syngeneic transplant control (B6 to B6) and APRIL/BLyS blockade treated animals (p = 0.90). Additionally, disruption of splenic germinal center architecture was noted in the APRIL/BLyS blockade treated animals. Despite the significant decrease in autoantibody production and germinal center disruption, no significant difference in lymphocyte infiltration was noted in the transplanted kidney. APRIL/BLyS blockade resulted in a significant decrease of autoantibody production and disrupted splenic germinal center formation in a chronic kidney transplant model, however in this model no difference in kidney transplant pathology was seen, which may have to do with the absence of any T cell centric immunosuppression. Regardless, these findings suggest that APRIL/BLyS blockade may play a role in decreasing antibody formation long-term in kidney transplantation. Future investigations will use APRIL/BLyS blockade in conjunction with T lymphocyte depleting agents to determine its efficacy in chronic rejection.
Highlights
Antibody mediated rejection (AMR) is widely recognized as a common cause for late kidney allograft failure.[1,2,3] Mature B lymphocytes and plasma cells play a critical role in the development of AMR through donor specific antibody (DSA) production, but they function as effector cells in T lymphocyte activation, which may result in cellular rejection.[4, 5] Current strategies used to treat AMR include antiCD20 antibodies, antibody removal, and proteasome inhibitors to target plasma cells, which are the producers of alloantibody. [6, 7] Despite these efforts, chronic antibody mediated rejection remains a significant barrier to achieving long-term graft survival in kidney transplantation
APRIL/BLyS blockade resulted in a significant decrease of autoantibody production and disrupted splenic germinal center formation in a chronic kidney transplant model, in this model no difference in kidney transplant pathology was seen, which may have to do with the absence of any T cell centric immunosuppression. Regardless, these findings suggest that APRIL/BLyS blockade may play a role in decreasing antibody formation long-term in kidney transplantation
Animal health was evaluated by activity level, weight gain or loss, Autoantibody production decreased with APRIL/BLyS blockade in murine kidney transplant model hunched posture, and other signs of distress
Summary
Antibody mediated rejection (AMR) is widely recognized as a common cause for late kidney allograft failure.[1,2,3] Mature B lymphocytes and plasma cells (terminally differentiated B lymphocytes) play a critical role in the development of AMR through donor specific antibody (DSA) production, but they function as effector cells in T lymphocyte activation, which may result in cellular rejection.[4, 5] Current strategies used to treat AMR include antiCD20 antibodies (rituximab), antibody removal (plasmapheresis, intravenous immunoglobulin), and proteasome inhibitors to target plasma cells, which are the producers of alloantibody. [6, 7] Despite these efforts, chronic antibody mediated rejection (cAMR) remains a significant barrier to achieving long-term graft survival in kidney transplantation. A recent randomized-controlled trial investigated the efficacy of anti-BLyS antibody (belimumab, GlaxoSmithKline) in addition to standard-of-care immunosuppression to reduce naïve B cells. This endpoint was not met, belimumab reduced memory B cells, which suggests it may have a role in long-term desensitization strategies in patients with pre-existing DSA.[13] B cell maturation antigen (BCMA), which APRIL and BLyS bind to on the surface of memory B and plasma cells, has been targeted in multiple myeloma clinical trials using anti-BCMA antibody with promising results.[14, 15]
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