Allosensitization does not increase the risk of xenoreactivity to alpha1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists.
BACKGROUND
The recent availability of alpha1,3-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.
Wong
Banny S
BS
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, 02129, USA.
Yamada
Kazuhiko
K
Okumi
Masayoshi
M
Weiner
Joshua
J
O'Malley
Patricia E
PE
Tseng
Yau-Lin
YL
Dor
Frank J M F
FJ
Cooper
David K C
DK
Saidman
Susan L
SL
Griesemer
Adam
A
Sachs
David H
DH
D000818:Animals; D000906:Antibodies / Q000276:immunology; D004226:Dithioerythritol / Q000494:pharmacology; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D012307:Risk Factors; D013552:Swine / Q000276:immunology; D013556:Swine, Miniature / Q000235:genetics / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*; D014850:Waiting Lists
D000906:Antibodies; D004226:Dithioerythritol; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase