The α-gal epitope (Galα1-3Galβ1-4GlcNAc-R) in xenotransplantation

Galili, Uri

doi:10.1016/s0300-9084(01)01294-9

Cited by 197 publications

(160 citation statements)

References 66 publications

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“…Furthermore, the growing tissue makes use of host vasculature, and thereby evades hyperacute or acute rejection, which could potentially be mediated by preexisting anti-pig antibodies (10). This finding supports our working hypothesis that growing the embryonic pig tissue de novo within the NHP recipient, provides an advantageous source for organ transplantation compared to adult pig organ transplantation, which requires anastomosis of donor blood vessels.…”

Section: Discussionsupporting

confidence: 77%

“…However, considering that xenogeneic transplantation into primates is far more complex, due to preexisting anti-porcine antibodies, studies in a nonhuman primate (NHP) model for diabetes were required. Our working hypothesis, suggesting that embryonic tissue transplantation would not be adversely affected by such a humoral response was based on 2 major observations: (i) hyperacute and acute rejection are mainly mediated by complement activation in blood vessels, mediated by preformed anti-pig antibodies recognizing ␣-gal and other carbohydrates expressed on endothelial cells (10), and (ii) data from our mouse studies showing that the embryonic implants predominantly induce host-type vasculature to support their growth and development in the recipient, resulting in an organ comprised mainly of porcine epithelial cells and host endothelium.…”

mentioning

confidence: 99%

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Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

Hecht

Eventov‐Friedman

Rosen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Xenotransplantation of pig tissues has great potential to overcome the shortage of organ donors. One approach to address the vigorous immune rejection associated with xenotransplants is the use of embryonic precursor tissue, which induces and utilizes host vasculature upon its growth and development. Recently, we showed in mice that embryonic pig pancreatic tissue from embryonic day 42 (E42) exhibits optimal properties as a ␤ cell replacement therapy. We now demonstrate the proof of concept in 2 diabetic Cynomolgus monkeys, followed for 393 and 280 days, respectively. A marked reduction of exogenous insulin requirement was noted by the fourth month after transplantation, reaching complete independence from exogenous insulin during the fifth month after transplantation, with full physiological control of blood glucose levels. The porcine origin of insulin was documented by a radioimmunoassay specific for porcine C-peptide. Furthermore, the growing tissue was found to be predominantly vascularized with host blood vessels, thereby evading hyperacute or acute rejection, which could potentially be mediated by preexisting anti-pig antibodies. Durable graft protection was achieved, and most of the late complications could be attributed to the immunosuppressive protocol. While fine tuning of immune suppression, tissue dose, and implantation techniques are still required, our results demonstrate that porcine E-42 embryonic pancreatic tissue can normalize blood glucose levels in primates. Its long-term proliferative capacity, its revascularization by host endothelium, and its reduced immunogenicity, strongly suggest that this approach could offer an attractive replacement therapy for diabetes.immune-suppression ͉ rejection ͉ xeno-transplantation

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 99%

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

Hecht

Eventov‐Friedman

Rosen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…However, there are anti-Gal antibodies in human blood. Therefore, transplantation of pig organs into humans causes a hyperacute rejection response, which is a major barrier for pig-to-human transplantation [10][11][12]. Gal epitopes are catalyzed by α-1, 3-galactosyltransferase (GGTA1).…”

mentioning

confidence: 99%

Generation of GGTA1 biallelic knockout pigs via zinc-finger nucleases and somatic cell nuclear transfer

Bao

Chen

Jong

et al. 2014

Sci. China Life Sci.

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Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs. Conventional gene targeting in pig somatic cells is extremely inefficient. Zinc-finger nuclease (ZFN) technology has been shown to be a powerful tool for efficiently inducing mutations in the genome. However, ZFN-mediated targeting in pigs has rarely been achieved. Here, we used ZFNs to knock out the porcine α-1,3-galactosyl-transferase (GGTA1) gene, which generates Gal epitopes that trigger hyperacute immune rejection in pig-to-human transplantation. Primary pig fibroblasts were transfected with ZFNs targeting the coding region of GGTA1. Eighteen mono-allelic and four biallelic knockout cell clones were obtained after drug selection with efficiencies of 23.4% and 5.2%, respectively. The biallelic cells were used to produce cloned pigs via somatic cell nuclear transfer (SCNT). Three GGTA1 null piglets were born, and one knockout primary fibroblast cell line was established from a cloned fetus. Gal epitopes on GGTA1 null pig cells were completely eliminated from the cell membrane. Functionally, GGTA1 knockout cells were protected from complement-mediated immune attacks when incubated with human serum. This study demonstrated that ZFN is an efficient tool in creating gene-modified pigs. GGTA1 null pigs and GGTA1 null fetal fibroblasts would benefit research and pig-to-human transplantation.pig, xenotransplantation, ZFNs, GGTA1, biallelic knockout, SCNT Citation:

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“…It could also lead to pig clones with such genes inactivated by "knock-out" technique (homologous recombination; Figure 1). This involves encoding enzymes which catalyse the addition of different antigenic determinant fragments (xenogeneic oligosaccharide residues) to the plasma membrane glycoproteins and glycolipids (for example α-1,3-GT allele, locus GGTA1), that are responsible for hyperacute vascular rejection (HAR) of xenografts (xenogeneic transplants), as a result of immunoreaction with human preformed xenoreactive antibodies (mainly anti-Gal antibodies, directed against galactosyl-α-1,3-galactose epitopes on the surface of porcine endothelial graft cells; Joziasse and Oriol, 1999;Galili, 2001;Thomson et al, 2003). Transgenesis (with application of gene targeting; Figure 1), in conjuction with somatic cloning, could provide, in the near future, a basis for the generation and multiplication of a pig population with such genetically transformed ("humanized") immunological system and blocked expression of many epitopes.…”

Section: The Possibilities Of Practical Application Of Pig Somatic CLmentioning

confidence: 99%

Development of pig cloning studies: past, present and future

Samiec¹

2004

J. Anim. Feed Sci.

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The birth of the first nuclear transfer-derived cloned piglet resulted from the transfer of a nucleus from a 4-cell stage embryo to an enucleated oocyte. Although biotechnological procedures in swine have recently undergone tremendous progress, the efficiency of pig somatic cloning is still lower than in other species of farm animals and, when expressed as a proportion of reconstructed oocytes, it does not exceed an average of 5 to 10% blastocysts and 1.5% born piglets. The basic prerequisite for practical application of this method is to improve efficiency. This requires further detailed studies. Development of pig somatic cell cloning was inspired not only by the necessity for quick improvement of the efficiency of the nuclear transfer technique in this species, but above all by its possible practical application for multiplication of transgenic piglets, for use in transplantation medicine and immunology, also pharmacy and animal breeding. A deficit of organs for human allotransplantation became a stimulus to the search for new, alternative sources of grafts. Therefore, a particularly attractive aspect of pig somatic cloning is the possibility of generating large numbers of transgenic pig organs for xenotransplantation. Compatibility with the human ones in size, anatomy, and physiology makes this an attractive proposition.

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The α-gal epitope (Galα1-3Galβ1-4GlcNAc-R) in xenotransplantation

Cited by 197 publications

References 66 publications

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

Generation of GGTA1 biallelic knockout pigs via zinc-finger nucleases and somatic cell nuclear transfer

Development of pig cloning studies: past, present and future

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