Article

Allosensitization Does Not Increase the Risk of Xenoreactivity to α1,3-Galactosyltransferase Gene-Knockout Miniature Swine in Patients on Transplantation Waiting Lists

Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, 02129, USA.
Transplantation (Impact Factor: 3.78). 09/2006; 82(3):314-9. DOI: 10.1097/01.tp.0000228907.12073.0b
Source: PubMed

ABSTRACT 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.
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.
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.
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.

Download full-text

Full-text

Available from: Frank Dor, Jul 03, 2015
1 Follower
 · 
135 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Work on delay tolerant networking has grown out of work on an interplanetary Internet and aims to provide a type of network stack which is specifically designed for use in networks with inherently long transit times - often also involving highly constrained network nodes. We present an update on progress with this technology and describe how it might be used to construct a flexible network to support both one type of Earth-based sensor network as well as future space applications.
    Recent Advances in Space Technologies, 2003. RAST '03. International Conference on. Proceedings of; 12/2003
  • [Show abstract] [Hide abstract]
    ABSTRACT: Baertschiger RM, Buhler LH. Xenotransplantation literature update July–August, 2006.Xenotransplantation 2006; 13: 571–575. © Blackwell Munksgaard, 2006
    Xenotransplantation 12/2006; 13(6):571-5. DOI:10.1111/j.1399-3089.2006.00356.x
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The production of alpha1,3-galactosyltransferase gene-knockout (GT-KO) pigs has overcome the barrier of preformed anti-Galalpha1,3Gal (Gal) antibodies that has inhibited progress in pig-to-primate organ xenotransplantation for many years. Survival of GT-KO pig organs in nonhuman primates is currently limited by the development of a thrombotic microangiopathy that results in increasing ischemic injury of the transplanted organ over weeks or months. Potential causative factors include vascular endothelial activation from preformed anti-nonGal antibodies or cells of the innate immune system that recognize nonGal pig antigens directly, and coagulation dysregulation associated with molecular incompatibilities between pig and primate. Carefully isolated pancreatic islets from wild-type (genetically unmodified) adult pigs express minimal Gal epitopes, allowing survival sometimes for weeks or months after transplantation into nonhuman primates receiving immunosuppression directed only at T-cell function. However, there is a considerable immediate loss of islets, probably related to activation of coagulation and complement cascades. Further genetic manipulation of organ-source pigs is therefore required to overcome these problems. GT-KO pigs expressing a human complement-regulatory protein, e.g. decay-accelerating factor, and/or an 'anti-coagulant' gene, e.g. human tissue factor pathway inhibitor, might prevent the change in vascular endothelium from an anti-coagulant to a procoagulant phenotype, and protect the islets from early loss.
    Transplant International 03/2007; 20(2):107-17. DOI:10.1111/j.1432-2277.2006.00398.x