Abrogation of anti-HLA antibodies via proteasome inhibition.
BACKGROUND
Current treatments for autoantibody-mediated diseases (i.e., systemic lupus erythematosus) and alloantibodies (in transplant) are minimally effective. Although they deplete naïve B cells, plasmablasts, and transiently reduce antibody concentrations, they are minimally effective against long-lived, antibody-producing plasma cells. In transplantation, plasma cells produce antibodies directed against human leukocyte antigen (HLA) antigens causing poor allograft survival. We report the first clinical experience with a plasma cell depleting therapy, bortezomib, to abrogate anti-HLA antibodies in transplantation (outside of rejection) in an attempt to improve long-term allograft survival.


METHODS
Eleven patients with anti-HLA alloantibodies were treated with bortezomib. All patients underwent plasmapheresis to aid in removal of antibodies and to determine the effect of bortezomib. Serial measurements of anti-HLA antibody levels were conducted weekly by single antigen bead on Luminex platform.


RESULTS
Bortezomib treatment elicited substantial reduction in both donor-specific antibody (DSA) and non-DSA levels. Antibodies were directed against DSA in 8 of 11 cases. Mean time to antibody appearance was 2 months posttransplant. Within 22 days (median) from treatment initiation, 9 of 11 patients' antibody levels dropped to less than 1000 mean fluorescence intensity. Of two patients without successful depletion, all had peak mean fluorescence intensity more than 10,000. At a mean follow-up of approximately 4 months posttreatment, all patients have stable graft function. Minimal transient side effects were noticed with bortezomib in the form of gastrointestinal toxicity, thrombocytopenia, and paresthesias.


CONCLUSIONS
Bortezomib therapy effectively abrogates anti-HLA antibodies. Hence, removal of antibodies, by proteasome inhibition, represents a new treatment strategy for transplantation and may have benefit in autoimmune-related disease.
Trivedi
Hargovind L
HL
Department of Nephrology and Transplantation Medicine, Institute of Kidney Diseases and Research Centre-Institute of Transplantation Sciences, Ahmedabad, Gujarat, India. ikdrcad1@sancharnet.in
Terasaki
Paul I
PI
Feroz
Aziz
A
Everly
Matthew J
MJ
Vanikar
Aruna V
AV
Shankar
Vangipurapu
V
Trivedi
Varsha B
VB
Kaneku
Hugo
H
Idica
Adam K
AK
Modi
Pranjal R
PR
Khemchandani
Sajani I
SI
Dave
Shruti D
SD
D000328:Adult; D001897:Boronic Acids / Q000276:immunology / Q000627:therapeutic use; D000069286:Bortezomib; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006681:HLA-D Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000097:blood* / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D019520:Living Donors; D008297:Male; D011480:Protease Inhibitors / Q000276:immunology / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000276:immunology / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000276:immunology; D055815:Young Adult
D001897:Boronic Acids; D006680:HLA Antigens; D006681:HLA-D Antigens; D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex