Background: Despite major advances in transplant medicine, antibody-mediated rejection (AMR) continues
to have severe clinical implications and adversely affect graft survival. Therefore, the search for alternative drugs
to treat AMR is widely pursued. The first-in-class proteasome inhibitor bortezomib (BZ) is a selective inhibitor of
the 26S proteasome, which was initially approved for the treatment of malignant plasma cell disorders.
Methods: This review encompasses how our understanding of inhibiting proteasome pathway created the basis of
BZ research and important milestones accomplished in AMR treatment in the transplant setting. It further discusses
at length the results of clinical studies, the tolerability profile, drug-drug interactions and the perspectives of BZ use
in desensitization protocols.
Results: Proteasome inhibition can downregulate NF-κB activity; decrease cell proliferation/differentiation; induce
apoptosis via cell cycle arrest, endoplasmic reticulum stress and caspase induction due the accumulation of unfolded
or misfolded proteins; and downregulate antigen presentation, cell-cell interaction, and cell migration. Proteasome
inhibition is more evident in cells with high rate of protein synthesis and secretion, like plasma cells. These cells
play a critical role in the production of antibodies during AMR.
Conclusions: There is accumulating evidence that the proteasome inhibitor BZ may substantially affect the function
and integrity of alloantibody-secreting plasma cells in AMR after organ solid transplant, as well as the activation,
proliferation and differentiation of T- and B-lymphocytes. Recent clinical studies have provided evidence that BZ
has the capability to downregulate circulating antibodies and treat AMR episodes. Additional randomized-controlled
studies are required to assess the impact of BZ during short and long follow-ups.