Proteasome inhibition by bortezomib: effect on HLA-antibody levels and specificity in sensitized patients awaiting renal allograft transplantation.
BACKGROUND
Sensitization to human leukocyte antigen (HLA) prolongs waiting list time and reduces allograft survival in solid organ transplantation. Current strategies for pretransplant desensitization are based on B-cell depletion and extracorporeal treatment. The proteasome inhibitor bortezomib allows direct targeting of the antibody-producing plasma cell and has been used in antibody-mediated rejection (AMR) and recipient desensitization with varying results. Here, we report the effect of bortezomib preconditioning on HLA antibody titers and specificity in highly sensitized patients awaiting renal allograft transplantation.


METHODS
Two highly sensitized patients awaiting third kidney transplantation were given one cycle of bortezomib (1.3 mg/m², days 1, 4, 8, 11), as part of recipient desensitization. Time-course and levels of anti-HLA antibodies, as well as specificity to previous transplant antigens were monitored by luminex technology. In addition, measles and tetanus toxoid immunoglobulin G (IgG) was measured.


RESULTS
Following bortezomib, overall changes in IgG levels were small and no sustained reduction in anti-HLA class I or II antibody levels was observed over more than 100 days of follow-up to both, donor specific and non-donor specific antigens. Moreover, anti-measles and -tetanus toxoid IgG levels remained unchanged.


CONCLUSIONS
Bortezomib preconditioning alone does not result in sustained reduction of HLA antibody levels or alter protective immunity in sensitized patients. This supports the notion, that bortezomib requires activation of plasma cells, as in AMR, to effectively reduce HLA antibody production. Hence, in a pretransplant setting, combination strategies may be required to derive benefit from proteasome inhibition.
Department of Endocrinology and Diabetology, Angiology, Nephrology and Clinical Chemistry, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
Martina
M
Guthoff
Barbara
B
Schmid-Horch
Katja C
KC
Weisel
Hans-Ulrich
HU
Häring
Alfred
A
Königsrainer
Nils
N
Heyne
D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D000939:Epitopes / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D010950:Plasma Cells / Q000187:drug effects* / Q000276:immunology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D012086:Reoperation; D019172:Transplantation Conditioning
D001897:Boronic Acids; D000939:Epitopes; D006680:HLA Antigens; D007074:Immunoglobulin G; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib