Abstract
Alloantibody represents a significant barrier in kidney transplant through the sensitization of patients prior to transplant through antibody mediated rejection (ABMR). APRIL BLyS are critical survival factors for mature B lymphocytes plasma cells, the primary source of alloantibody. We examined the effect of APRIL/BLyS blockade via TACI-Ig (Transmembrane activator calcium modulator cyclophilin lig interactor-Immunoglobulin) in a preclinical rodent model as treatment for both desensitization ABMR. Lewis rats were sensitized with Brown Norway (BN) blood for 21 days. Following sensitization, animals were then sacrificed or romized into kidney transplant (G4, sensitized transplant control); desensitization with TACI-Ig followed by kidney transplant (G5, sensitized + pre-transplant TACI-Ig); kidney transplant with post-transplant TACI-Ig for 21 days (G6, sensitized + post-transplant TACI-Ig); desensitization with TACI-Ig followed by kidney transplant post-transplant TACI-Ig for 21 days (G7, sensitized + pre- post-transplant TACI-Ig). Animals were sacrificed on day 21 post-transplant tissues were analyzed using flow cytometry, IHC, ELISPOT, RT-PCR. Sensitized animals treated with APRIL/BLyS blockade demonstrated a significant decrease in marginal zone non-switched B lymphocyte populations (p<0.01). Antibody secreting cells were also significantly reduced in the sensitized APRIL/BLyS blockade treated group. Post-transplant APRIL/BLyS blockade treated animals were found to have significantly less C4d deposition less ABMR as defined by Banff classification when compared to groups receiving APRIL/BLyS blockade before transplant or both before after transplant (p<0.0001). The finding of worse ABMR in groups receiving APRIL/BLyS blockade before both before after transplant may indicate that B lymphocyte depletion in this setting also resulted in regulatory lymphocyte depletion resulting in a worse rejection. Data presented here demonstrates that the targeting of APRIL BLyS can significantly deplete mature B lymphocytes, antibody secreting cells, effectively decrease ABMR when given post-transplant in a sensitized animal model.
Highlights
Despite the fact that current one-year kidney allograft survival remains above 90%, little improvement has been made in long-term graft survival.[1]
In order to evaluate the efficacy of APRIL/BLyS blockade as a method to desensitize patients prevent antibody mediated rejection (ABMR), we began with the assessment of plasma cell presence functionality
APRIL/BLyS blockade resulted in a profound depletion of IgM IgG secreting cells across spleen bone marrow when compared to non-sensitized sensitized untreated animals (Fig 3)
Summary
Despite the fact that current one-year kidney allograft survival remains above 90%, little improvement has been made in long-term graft survival.[1]. Sensitization occurs through blood transfusions, pregnancy, or prior transplants results in longer wait-times, increased death on the wait-list, inferior graft outcomes.[2,3,4] ABMR occurs as a result of preformed alloantibody against the graft or through the development of de novo donor specific antibody (dnDSA).[5,6,7] a multitude of pharmacologic therapies exist to target B lymphocytes at various stages of development, current therapies have failed to effectively treat acute chronic ABMR, which has resulted in a stagnate 10 year graft survival around 50% for patients receiving deceased donor kidney transplants.[1] A long-term solution to ABMR will likely need to focus on multiple targets, which may be achieved through the targeting of APRIL BLyS
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