Targeting the BAFF/APRIL Signalling Axis for Prevention of Antibody-Mediated Allograft Rejection.

Abstract

Introduction: B cell activating factor (BAFF) and its related cytokine APRIL are critical for B cell maturation. Here we study how their blockade influences heart graft survival in murine models of chronic antibody mediated rejection (AMR). Methods: BAFF blockade and combined Anti-BAFF/APRIL blockade was achieved by administering BAFFR-Ig or TACI-Ig. The impact of this blockade was examined in two murine models of germinal centre (GC) driven, chronic antibody-mediated rejection, whereby heart grafts were either (a) widely mismatched, eliciting anti-class I alloantibody; or (b) mismatched minimally at MHC class II only, eliciting autoantibody due to graft-versus-host activation of recipient B cells. Kinetics of graft rejection were monitored and humoral alloimmunity assessed by: immunohistochemical appraisal of splenic GC activity; quantification of splenic and bone marrow (BM) plasma cells (PCs); and assay of serum effector antibody. Results: BAFFR-Ig or TACI-Ig treatment of naive B6 mice induced profound depletion of mature B cells, and produced a B profile similar to that of mice genetically-deficient for BAFF-receptor. In either transplant model, even though B cell depletion was sustained, challenge with a heart allograft surprisingly provoked long-lasting class-switched effector antibody responses that resulted in endothelial C4d deposition, development of AV and eventual graft failure. In both models, GC responses were abrogated by BAFF blockade, with either marked reductions in, or a virtual absence of, antigen-specific BM long-lived PCs following administration of BAFFR-Ig or TACI-Ig, respectively. The source of antibody instead appeared to be splenic extrafollicular responses, because numbers of antigen-specific splenic PCs were not affected by BAFFR-Ig therapy, and only slightly reduced with TACI-Ig therapy. This escape and extrafollicular activation of alloreactive B cells does not reflect sub-optimal BAFF and APRIL blockade, because similar responses were observed following challenge of BAFF-receptor deficient mice. Conclusion: Even though BAFF blockade can effectively deplete the mature B cell compartments and prevent GC humoral immunity, concurrent alloantigen challenge provokes a limited extrafollicular response that can nevertheless mediate chronic AMR and lead to eventual graft failure.