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Mary Carmelle Philogene, Paul Sikorski, Robert A. Montgomery, Mary S. Leffell, and Andrea A. Zachary

Background. Bortezomib has been used to reduce HLA antibody in patients either before transplantation or as treatment
for antibody-mediated rejection (AMR). Reports on its efficacy show mixed results. The mechanism of action
of this agent is via proteasome inhibition. The primary route of synthesis of HLA class I molecules is dependent on
peptide generation by the proteasome, whereas that of class II is not. We observed a differential effect of bortezomib on
class I versus class II antibody and hypothesized that this was related to a reduced expression of class I HLA antigens.
Methods. The effect of bortezomib on HLA antibody levels was evaluated in 13 patients who were desensitized for
incompatible renal transplantation. We calculated the percent difference in HLA antibody level before and after bortezomib
treatment and the impact of bortezomib on HLA expression in lymphocytes of healthy control subjects.
Results. On average, the level of HLA class I donor-specific antibody (DSA) decreased by 32%, whereas that of class II
DSA increased by 29%. In vitro bortezomib treatment of lymphocytes resulted in a mean decrease of 23% in MHC
class I expression on B lymphocytes and no change (+1.08%) in MHC class II expression (P=0.0003). The amount
of intracellular class I molecules was reduced by a mean of 29% with bortezomib.
Conclusion. These data indicate that bortezomib reduces HLA class I antibody more effectively than class II antibody.
This difference may be due to the reduced expression of class I molecules resulting from treatment with this proteasome
inhibitor.

Keywords: Bortezomib, HLA antibody, Renal transplantation, Proteasome inhibition, MHC molecules.

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