BACKGROUND: Bortezomib, a proteasome inhibitor used to treat multiple myeloma, has been administered (± plasma exchange ± intravenous immunoglobulin [IVIg]) in attempts to reduce antibodies against human leukocyte antigens (HLA) in sensitized patients undergoing organ transplantation. To our knowledge, bortezomib has not been investigated for its effect on natural anti-pig antibodies. If bortezomib could reduce the production of anti-pig antibodies, this would likely be beneficial to the outcome of pig organ grafts in primates. METHODS: Nine patients received bortezomib either to reduce anti-HLA antibody levels before organ allotransplantation or to treat antibody-mediated rejection. Patients at the Mayo Clinic (Group 1; n = 4) received bortezomib alone, whereas at the UPMC (Group 2; n = 5), this was combined with plasmaphereses ± IVIg in some cases. Anti-pig IgM and IgG levels against wild-type (WT) and α1,3-galactosyltransferase gene knockout (GTKO) pig aortic endothelial cells (flow cytometry-relative mean fluorescence intensity) and anti-Gal IgM and IgG (ELISA-OD480 nm ) were measured pre- and post-bortezomib therapy. RESULTS: Mean anti-pig IgM levels were 11.2 (WT) and 1.9 (GTKO) pre-bortezomib treatment and 9.4 (WT: P = 0.02) and 1.7 (GTKO: P = 0.33) post-bortezomib treatment, respectively. Mean anti-pig IgG levels were 4.3 (WT) and 1.5 (GTKO) pre-bortezomib treatment and 3.6 (WT: P = 0.21) and 1.4 (GTKO: P = 0.20) post-bortezomib treatment, respectively. Mean anti-Gal IgM and IgG levels were 0.7 and 1.1, respectively, pre-treatment, and 0.6 (P = 0.03) and 1.1 (NS), respectively, post-treatment. When the data were analyzed in Groups 1 and 2 separately, there were no significant differences between the pre- and post-bortezomib levels of anti-pig, anti-non-Gal, or anti-Gal IgM or IgG. CONCLUSIONS: From this limited study, we conclude that bortezomib might reduce anti-Gal IgM levels in primates, but, in this respect alone, is unlikely to have any significant effect on the outcome of GTKO pig organ transplantation.
BACKGROUND:Bortezomib, a proteasome inhibitor used to treat multiple myeloma, has been administered (± plasma exchange ± intravenous immunoglobulin [IVIg]) in attempts to reduce antibodies against human leukocyte antigens (HLA) in sensitized patients undergoing organ transplantation. To our knowledge, bortezomib has not been investigated for its effect on natural anti-pig antibodies. If bortezomib could reduce the production of anti-pig antibodies, this would likely be beneficial to the outcome of pig organ grafts in primates. METHODS: Nine patients received bortezomib either to reduce anti-HLA antibody levels before organ allotransplantation or to treat antibody-mediated rejection. Patients at the Mayo Clinic (Group 1; n = 4) received bortezomib alone, whereas at the UPMC (Group 2; n = 5), this was combined with plasmaphereses ± IVIg in some cases. Anti-pigIgM and IgG levels against wild-type (WT) and α1,3-galactosyltransferase gene knockout (GTKO) pig aortic endothelial cells (flow cytometry-relative mean fluorescence intensity) and anti-GalIgM and IgG (ELISA-OD480 nm ) were measured pre- and post-bortezomib therapy. RESULTS: Mean anti-pigIgM levels were 11.2 (WT) and 1.9 (GTKO) pre-bortezomib treatment and 9.4 (WT: P = 0.02) and 1.7 (GTKO: P = 0.33) post-bortezomib treatment, respectively. Mean anti-pig IgG levels were 4.3 (WT) and 1.5 (GTKO) pre-bortezomib treatment and 3.6 (WT: P = 0.21) and 1.4 (GTKO: P = 0.20) post-bortezomib treatment, respectively. Mean anti-GalIgM and IgG levels were 0.7 and 1.1, respectively, pre-treatment, and 0.6 (P = 0.03) and 1.1 (NS), respectively, post-treatment. When the data were analyzed in Groups 1 and 2 separately, there were no significant differences between the pre- and post-bortezomib levels of anti-pig, anti-non-Gal, or anti-GalIgM or IgG. CONCLUSIONS: From this limited study, we conclude that bortezomib might reduce anti-GalIgM levels in primates, but, in this respect alone, is unlikely to have any significant effect on the outcome of GTKO pig organ transplantation.
Authors: D Harper; B Gollackner; Y Xu; D Calderhead; D Ryan; W Li; J Cheng; C Wu; K Moran; D Latinne; H Bazin; M E White-Scharf; D K C Cooper; M Awwad; J Chang Journal: Xenotransplantation Date: 2004-01 Impact factor: 3.907
Authors: I P Alwayn; Y Xu; M Basker; C Wu; L Buhler; D Lambrigts; S Treter; D Harper; H Kitamura; E S Vitetta; S Abraham; M Awwad; M E White-Scharf; D H Sachs; A Thall; D K Cooper Journal: Xenotransplantation Date: 2001-08 Impact factor: 3.907
Authors: L Bühler; M Basker; I P Alwayn; C Goepfert; H Kitamura; T Kawai; S Gojo; T Kozlowski; F L Ierino; M Awwad; D H Sachs; R Sackstein; S C Robson; D K Cooper Journal: Transplantation Date: 2000-11-15 Impact factor: 4.939
Authors: B Gollackner; D Ryan; C Knosalla; M Basker; I P J Alwayn; D Harper; G Salomon; S Mauiyyedi; L Correa; A Thall; D K C Cooper Journal: Xenotransplantation Date: 2003-01 Impact factor: 3.907
Authors: Bernd Gollackner; Seo Kiat Goh; Imrana Qawi; Leo Buhler; Christoph Knosalla; Soizic Daniel; Elzbieta Kaczmarek; Michel Awwad; David K C Cooper; Simon C Robson Journal: Transplantation Date: 2004-06-15 Impact factor: 4.939
Authors: Stuart L Houser; Kenji Kuwaki; Christoph Knosalla; Frank J M F Dor; Bernd Gollackner; Jane Cheng; Akira Shimizu; Henk-Jan Schuurman; David K C Cooper Journal: Xenotransplantation Date: 2004-09 Impact factor: 3.907