Abrogation of Anti-HLA Antibodies via Proteasome Inhibition

被引:139
作者
Trivedi, Hargovind L. [1 ]
Terasaki, Paul I. [2 ]
Feroz, Aziz [1 ]
Everly, Matthew J. [2 ]
Vanikar, Aruna V. [3 ]
Shankar, Vangipurapu [4 ,5 ]
Trivedi, Varsha B. [3 ]
Kaneku, Hugo [2 ]
Idica, Adam K. [6 ]
Modi, Pranjal R. [7 ]
Khemchandani, Sajani I. [7 ]
Dave, Shruti D. [3 ]
机构
[1] Inst Kidney Dis & Res Ctr, Dept Nephrol & Transplantat Med, ITS, Ahmadabad 380016, Gujarat, India
[2] Terasaki Fdn Lab, Los Angeles, CA USA
[3] Inst Kidney Dis & Res Ctr, Dept Pathol, ITS, Lab Med Transfus Serv & Immunohematol, Ahmadabad 380016, Gujarat, India
[4] Shri Krishna Hosp, Dept Radiat Oncol, MS Patel Canc Ctr, Anand, Gujarat, India
[5] Med Res Ctr, Anand, Gujarat, India
[6] One Lambda Inc, Canoga Pk, CA USA
[7] Inst Kidney Dis & Res Ctr, Dept Urol & Transplantat, ITS, Ahmadabad 380016, Gujarat, India
关键词
Proteasome inhibitor; Bortezomib; NF-kB; Plasma cell; B cell; Alloantibodies; HLA; Transplantation; PLASMA-CELLS; ACUTE REJECTION; MYELOMA CELLS; B-CELLS; BORTEZOMIB; APOPTOSIS; PHASE-2; DISEASE; RISK;
D O I
10.1097/TP.0b013e3181a4b91b
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Current treatments for autoantibody-mediated diseases (i.e., systemic lupus erythematosus) and alloantibodies (in transplant) are minimally effective. Although the), deplete naive 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 all 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 I I 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.
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收藏
页码:1555 / 1561
页数:7
相关论文
共 30 条
[1]   The proteasome: A suitable antineoplastic target [J].
Adams, J .
NATURE REVIEWS CANCER, 2004, 4 (05) :349-360
[2]   Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization [J].
Blink, EJ ;
Light, A ;
Kallies, A ;
Nutt, SL ;
Hodgkin, PD ;
Tarlinton, DM .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 201 (04) :545-554
[3]   Alloantibody Levels and Acute Humoral Rejection Early After Positive Crossmatch Kidney Transplantation [J].
Bums, J. M. ;
Comell, L. D. ;
Perry, D. K. ;
Pollinger, H. S. ;
Gloor, J. M. ;
Kremers, W. K. ;
Gandhi, M. J. ;
Dean, P. G. ;
Stegall, M. D. .
AMERICAN JOURNAL OF TRANSPLANTATION, 2008, 8 (12) :2684-2694
[4]   A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib [J].
Chauhan, D ;
Catley, L ;
Li, GL ;
Podar, K ;
Hideshima, T ;
Velankar, M ;
Mitsiades, C ;
Mitsiades, N ;
Yasui, H ;
Letai, A ;
Ovaa, H ;
Berkers, C ;
Nicholson, B ;
Chao, TH ;
Neuteboom, STC ;
Richardson, P ;
Palladino, MA ;
Anderson, KC .
CANCER CELL, 2005, 8 (05) :407-419
[5]   Proteasome-inhibited dendritic cells demonstrate improved presentation of exogenous synthetic and natural HLA-class I peptide epitopes [J].
Chromik, J ;
Schnürer, E ;
Meyer, RG ;
Wehler, T ;
Tüting, T ;
Wölfel, T ;
Huber, C ;
Herr, W .
JOURNAL OF IMMUNOLOGICAL METHODS, 2006, 308 (1-2) :77-89
[6]  
EVERLY M, 2008, TRANSPLANTATION, V86, P68
[7]   Bortezomib Provides Effective Therapy for Antibody- and Cell-Mediated Acute Rejection [J].
Everly, Matthew J. ;
Everly, Jason J. ;
Susskind, Brian ;
Brailey, Paul ;
Arend, Lois J. ;
Alloway, Rita R. ;
Roy-Chaudhury, Prabir ;
Govil, Amit ;
Mogilishetty, Gautham ;
Rike, Adele H. ;
Cardi, Michael ;
Wadih, George ;
Tevar, Amit ;
Woodle, E. Steve .
TRANSPLANTATION, 2008, 86 (12) :1754-1761
[8]  
Hideshima T, 2001, CANCER RES, V61, P3071
[9]   A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma [J].
Jagannath, S ;
Barlogie, B ;
Berenson, J ;
Siegel, D ;
Irwin, D ;
Richardson, PG ;
Niesvizky, R ;
Alexanian, R ;
Limentani, SA ;
Alsina, M ;
Adams, J ;
Kauffman, M ;
Esseltine, DL ;
Schenkein, DP ;
Anderson, KC .
BRITISH JOURNAL OF HAEMATOLOGY, 2004, 127 (02) :165-172
[10]   Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma [J].
Lonial, Sagar ;
Richardson, Paul G. ;
Miguel, Jesus San ;
Sonneveld, Pieter ;
Schuster, Michael W. ;
Blade, Joan ;
Cavenagh, Jamie ;
Rajkumar, S. Vincent ;
Jakubowiak, Andrzej J. ;
Esseltine, Dixie-Lee ;
Anderson, Kenneth C. ;
Harousseau, Jean-Luc .
BRITISH JOURNAL OF HAEMATOLOGY, 2008, 143 (02) :222-229