Autoantibody production significantly decreased with APRIL/BLyS blockade in murine chronic rejection kidney transplant model

Autoři: Natalie M. Bath aff001;  Xiang Ding aff001;  Bret M. Verhoven aff001;  Nancy A. Wilson aff002;  Lauren Coons aff001;  Adarsh Sukhwal aff001;  Weixiong Zhong aff003;  Robert R. Redfield III aff001
Působiště autorů: Department of Surgery, Division of Transplant, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff001;  Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, Unites States of America aff002;  Department of Pathology, University of Wisconsin–Madison, Madison, Wisconsin, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


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.

Klíčová slova:

B cells – Kidneys – Lymphocytes – Renal transplantation – T cells – Transplant rejection – Plasma cells


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2019 Číslo 10
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