Allosensitization does not increase the risk of xenoreactivity to α1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists

Banny S. Wong, Kazuhiko Yamada, Masayoshi Okumi, Joshua Weiner, Patricia E. O'Malley, Yau-Lin Tseng, Frank J.M.F. Dor, David K.C. Cooper, Susan L. Saidman, Adam Griesemer, David H. Sachs

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

BACKGROUND. The recent availability of α1,3-galactosyltransferase knockout (GalT-KO) miniature swine has eliminated anti-Gal antibodies as the major barrier to xenotransplantation, potentially bringing this modality closer to clinical application. Highly-allosensitized patients, who have poor prospects of receiving a suitable cross-match negative human organ, might be the first patients to benefit from xenotransplantation of porcine organs. However, concerns exist regarding cross-reactivity of alloreactive anti-human leukocyte antigen (HLA) antibodies against xenogeneic swine leukocyte antigen (SLA) antigens. We have investigated this question using sera from such patients on GalT-KO target cells. METHODS. Using flow cytometry and complement-dependent cytotoxicity (CDC) assays, we have tested a panel of 88 human serum samples from patients awaiting cadaveric renal allotransplantation for reactivity against: 1) human; 2) standard miniature swine; and 3) GalT-KO peripheral blood lymphocytes (PBL) and cultured endothelial cells. RESULTS. Anti-swine IgM and IgG antibody binding, as well as CDC, were significantly attenuated on GalT-KO versus standard swine. No correlation was found between the degree of anti-human panel reactive antibodies (PRA) and xenoreactivity against either standard or GalT-KO miniature swine. Treatment of sera with dithiothreitol (DTT) showed that the majority of remaining lymphocytotoxicity against GalT-KO swine was mediated by preformed IgM antibodies. Patients with high alloreactivity but low anti-GalT-KO xenoreactivity were readily identified. CONCLUSIONS. Highly allosensitized patients awaiting renal transplants appear to be at no increased risk of xenosensitization over their non-sensitized cohorts, and could therefore be candidates for xenotransplantation using GalT-KO swine donors.

Original languageEnglish
Pages (from-to)314-319
Number of pages6
JournalTransplantation
Volume82
Issue number3
DOIs
Publication statusPublished - 2006 Aug 18

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Galactosyltransferases
Miniature Swine
Gene Knockout Techniques
Waiting Lists
Transplantation
Swine
Heterologous Transplantation
Antibodies
Serum
Heterophile Antibodies
Kidney
Dithiothreitol
HLA Antigens
Immunoglobulin M
Anti-Idiotypic Antibodies
Cultured Cells
Flow Cytometry
Endothelial Cells
Tissue Donors
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Transplantation

Cite this

Wong, Banny S. ; Yamada, Kazuhiko ; Okumi, Masayoshi ; Weiner, Joshua ; O'Malley, Patricia E. ; Tseng, Yau-Lin ; Dor, Frank J.M.F. ; Cooper, David K.C. ; Saidman, Susan L. ; Griesemer, Adam ; Sachs, David H. / Allosensitization does not increase the risk of xenoreactivity to α1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists. In: Transplantation. 2006 ; Vol. 82, No. 3. pp. 314-319.
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title = "Allosensitization does not increase the risk of xenoreactivity to α1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists",
abstract = "BACKGROUND. The recent availability of α1,3-galactosyltransferase knockout (GalT-KO) miniature swine has eliminated anti-Gal antibodies as the major barrier to xenotransplantation, potentially bringing this modality closer to clinical application. Highly-allosensitized patients, who have poor prospects of receiving a suitable cross-match negative human organ, might be the first patients to benefit from xenotransplantation of porcine organs. However, concerns exist regarding cross-reactivity of alloreactive anti-human leukocyte antigen (HLA) antibodies against xenogeneic swine leukocyte antigen (SLA) antigens. We have investigated this question using sera from such patients on GalT-KO target cells. METHODS. Using flow cytometry and complement-dependent cytotoxicity (CDC) assays, we have tested a panel of 88 human serum samples from patients awaiting cadaveric renal allotransplantation for reactivity against: 1) human; 2) standard miniature swine; and 3) GalT-KO peripheral blood lymphocytes (PBL) and cultured endothelial cells. RESULTS. Anti-swine IgM and IgG antibody binding, as well as CDC, were significantly attenuated on GalT-KO versus standard swine. No correlation was found between the degree of anti-human panel reactive antibodies (PRA) and xenoreactivity against either standard or GalT-KO miniature swine. Treatment of sera with dithiothreitol (DTT) showed that the majority of remaining lymphocytotoxicity against GalT-KO swine was mediated by preformed IgM antibodies. Patients with high alloreactivity but low anti-GalT-KO xenoreactivity were readily identified. CONCLUSIONS. Highly allosensitized patients awaiting renal transplants appear to be at no increased risk of xenosensitization over their non-sensitized cohorts, and could therefore be candidates for xenotransplantation using GalT-KO swine donors.",
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Allosensitization does not increase the risk of xenoreactivity to α1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists. / Wong, Banny S.; Yamada, Kazuhiko; Okumi, Masayoshi; Weiner, Joshua; O'Malley, Patricia E.; Tseng, Yau-Lin; Dor, Frank J.M.F.; Cooper, David K.C.; Saidman, Susan L.; Griesemer, Adam; Sachs, David H.

In: Transplantation, Vol. 82, No. 3, 18.08.2006, p. 314-319.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Allosensitization does not increase the risk of xenoreactivity to α1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists

AU - Wong, Banny S.

AU - Yamada, Kazuhiko

AU - Okumi, Masayoshi

AU - Weiner, Joshua

AU - O'Malley, Patricia E.

AU - Tseng, Yau-Lin

AU - Dor, Frank J.M.F.

AU - Cooper, David K.C.

AU - Saidman, Susan L.

AU - Griesemer, Adam

AU - Sachs, David H.

PY - 2006/8/18

Y1 - 2006/8/18

N2 - BACKGROUND. The recent availability of α1,3-galactosyltransferase knockout (GalT-KO) miniature swine has eliminated anti-Gal antibodies as the major barrier to xenotransplantation, potentially bringing this modality closer to clinical application. Highly-allosensitized patients, who have poor prospects of receiving a suitable cross-match negative human organ, might be the first patients to benefit from xenotransplantation of porcine organs. However, concerns exist regarding cross-reactivity of alloreactive anti-human leukocyte antigen (HLA) antibodies against xenogeneic swine leukocyte antigen (SLA) antigens. We have investigated this question using sera from such patients on GalT-KO target cells. METHODS. Using flow cytometry and complement-dependent cytotoxicity (CDC) assays, we have tested a panel of 88 human serum samples from patients awaiting cadaveric renal allotransplantation for reactivity against: 1) human; 2) standard miniature swine; and 3) GalT-KO peripheral blood lymphocytes (PBL) and cultured endothelial cells. RESULTS. Anti-swine IgM and IgG antibody binding, as well as CDC, were significantly attenuated on GalT-KO versus standard swine. No correlation was found between the degree of anti-human panel reactive antibodies (PRA) and xenoreactivity against either standard or GalT-KO miniature swine. Treatment of sera with dithiothreitol (DTT) showed that the majority of remaining lymphocytotoxicity against GalT-KO swine was mediated by preformed IgM antibodies. Patients with high alloreactivity but low anti-GalT-KO xenoreactivity were readily identified. CONCLUSIONS. Highly allosensitized patients awaiting renal transplants appear to be at no increased risk of xenosensitization over their non-sensitized cohorts, and could therefore be candidates for xenotransplantation using GalT-KO swine donors.

AB - BACKGROUND. The recent availability of α1,3-galactosyltransferase knockout (GalT-KO) miniature swine has eliminated anti-Gal antibodies as the major barrier to xenotransplantation, potentially bringing this modality closer to clinical application. Highly-allosensitized patients, who have poor prospects of receiving a suitable cross-match negative human organ, might be the first patients to benefit from xenotransplantation of porcine organs. However, concerns exist regarding cross-reactivity of alloreactive anti-human leukocyte antigen (HLA) antibodies against xenogeneic swine leukocyte antigen (SLA) antigens. We have investigated this question using sera from such patients on GalT-KO target cells. METHODS. Using flow cytometry and complement-dependent cytotoxicity (CDC) assays, we have tested a panel of 88 human serum samples from patients awaiting cadaveric renal allotransplantation for reactivity against: 1) human; 2) standard miniature swine; and 3) GalT-KO peripheral blood lymphocytes (PBL) and cultured endothelial cells. RESULTS. Anti-swine IgM and IgG antibody binding, as well as CDC, were significantly attenuated on GalT-KO versus standard swine. No correlation was found between the degree of anti-human panel reactive antibodies (PRA) and xenoreactivity against either standard or GalT-KO miniature swine. Treatment of sera with dithiothreitol (DTT) showed that the majority of remaining lymphocytotoxicity against GalT-KO swine was mediated by preformed IgM antibodies. Patients with high alloreactivity but low anti-GalT-KO xenoreactivity were readily identified. CONCLUSIONS. Highly allosensitized patients awaiting renal transplants appear to be at no increased risk of xenosensitization over their non-sensitized cohorts, and could therefore be candidates for xenotransplantation using GalT-KO swine donors.

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