Targeting alloantibody production with bortezomib: does it make more sense?

The effectiveness of current therapies for humoral rejection and decreasing antibody production directed against human leukocyte antigens (HLA) remains controversial. Standard regimens are unable to abrogate alloantibody production long term, most likely due to a lack of a direct effect on inhibiting and depleting mature plasma cells. Bortezomib (BZ) may be more effective at removing long-lived plasma cells compared to standard regimens that modulate alloantibody production by different mechanisms. We report a kidney transplant recipient with several episodes of mixed antibody mediated and cellular rejection treated with numerous therapies including BZ. Monitoring included serial measurements of donor specific antibodies (DSA) by Luminex assay and repeated allograft biopsies. One cycle of BZ was able to reverse humoral rejection and graft dysfunction. DSA levels to multiple donor HLA antigens which were not affected by previous therapies were reduced to undetectable levels post BZ. Abrogation of DSA was only transient. Despite continued stable renal function post-BZ, the patient had a reemergence of DSA, and evidence of humoral rejection detected by allograft biopsy. Despite the promise of BZ as a therapy for humoral rejection, current data on how it should be used and its efficacy long-term remains limited.