Minimal effect of bortezomib in reducing anti-pig antibodies in human leukocyte antigen-sensitized patients: A pilot study

Hidetaka Hara, Andrew Bentall, Cassandra Long, Jason Fang, Oleg Andreyev, John Lunz, Mohamed Ezzelarab, Kareem M. Abu-Elmagd, Ron Shapiro, David Ayares, Mark D Stegall, David K C Cooper

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)429-437
Number of pages9
JournalXenotransplantation
Volume20
Issue number6
DOIs
StatePublished - Nov 2013

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HLA Antigens
Anti-Idiotypic Antibodies
Swine
Galactosyltransferases
Gene Knockout Techniques
Intravenous Immunoglobulins
Organ Transplantation
Bortezomib
Primates
Therapeutics
Antibodies
Proteasome Inhibitors
Plasma Exchange
Plasmapheresis
Multiple Myeloma
anti-IgM
Flow Cytometry
Endothelial Cells
Fluorescence
Enzyme-Linked Immunosorbent Assay

Keywords

  • antibodies, anti-Gal
  • antibodies, anti-nonGal
  • antibodies, anti-pig
  • bortezomib

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Minimal effect of bortezomib in reducing anti-pig antibodies in human leukocyte antigen-sensitized patients : A pilot study. / Hara, Hidetaka; Bentall, Andrew; Long, Cassandra; Fang, Jason; Andreyev, Oleg; Lunz, John; Ezzelarab, Mohamed; Abu-Elmagd, Kareem M.; Shapiro, Ron; Ayares, David; Stegall, Mark D; Cooper, David K C.

In: Xenotransplantation, Vol. 20, No. 6, 11.2013, p. 429-437.

Research output: Contribution to journalArticle

Hara, H, Bentall, A, Long, C, Fang, J, Andreyev, O, Lunz, J, Ezzelarab, M, Abu-Elmagd, KM, Shapiro, R, Ayares, D, Stegall, MD & Cooper, DKC 2013, 'Minimal effect of bortezomib in reducing anti-pig antibodies in human leukocyte antigen-sensitized patients: A pilot study', Xenotransplantation, vol. 20, no. 6, pp. 429-437. https://doi.org/10.1111/xen.12052
Hara, Hidetaka ; Bentall, Andrew ; Long, Cassandra ; Fang, Jason ; Andreyev, Oleg ; Lunz, John ; Ezzelarab, Mohamed ; Abu-Elmagd, Kareem M. ; Shapiro, Ron ; Ayares, David ; Stegall, Mark D ; Cooper, David K C. / Minimal effect of bortezomib in reducing anti-pig antibodies in human leukocyte antigen-sensitized patients : A pilot study. In: Xenotransplantation. 2013 ; Vol. 20, No. 6. pp. 429-437.
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abstract = "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.",
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AU - Long, Cassandra

AU - Fang, Jason

AU - Andreyev, Oleg

AU - Lunz, John

AU - Ezzelarab, Mohamed

AU - Abu-Elmagd, Kareem M.

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N2 - 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.

AB - 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.

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