Expression of the human α:1,2‐fucosyltransferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum‐mediated cytolysis

Costa, Cristina; Zhao, Lisa; Burton, Willis V.; Bondioli, K. R.; Williams, Barry L.; Hoagland, T.A.; DiTullio, Paul; Ebert, Karl M.; Fodor, William L.

doi:10.1096/fasebj.13.13.1762

Cited by 86 publications

(62 citation statements)

References 60 publications

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“…The report from Nextran (50) only analyzed a tail section of the transgenic pig. The next case was reported by Alexion Pharmaceuticals Inc. (51). They used a H2K b and a cytomegalovirus promoter and obtained a good expression of the ␣1,2FT gene in most of the transgenic pig tissues and analyzed the modified cell surface carbohydrates, mainly fibroblasts.…”

Section: Fig 5-continuedmentioning

confidence: 99%

Remodeling of the Major Pig Xenoantigen by N-Acetylglucosaminyltransferase III in Transgenic Pig

Miyagawa¹,

Murakami²,

Takahagi³

et al. 2001

Journal of Biological Chemistry

105

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We have been successful in generating several lines of transgenic mice and pigs that contain the human ␤-Dmannoside ␤-1,4-N-acetylglucosaminyltransferase III (GnT-III) gene. The overexpression of the GnT-III gene in mice and pigs reduced their antigenicity to human natural antibodies, especially the Gal␣1-3Gal␤1-4Glc-NAc-R, as evidenced by immunohistochemical analysis. Endothelial cell studies from the GnT-III transgenic pigs also revealed a significant down-regulation in antigenicity, including Hanganutziu-Deicher antigen, and dramatic reductions in both the complement-and natural killer cell-mediated pig cell lyses. Changes in the enzymatic activities of other glycosyltransferases, such as ␣1,3-galactosyltransferase, GnT-IV, and GnT-V, did not support cross-talk between GnT-III and these enzymes in the transgenic animals. In addition, we demonstrated the effect of GnT-III in down-regulating the xenoantigen of pig heart grafts, using a pig to cynomolgus monkey transplantation model, suggesting that this approach may be useful in clinical xenotransplantation in the future.

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Section: Fig 5-continuedmentioning

confidence: 99%

Remodeling of the Major Pig Xenoantigen by N-Acetylglucosaminyltransferase III in Transgenic Pig

Miyagawa¹,

Murakami²,

Takahagi³

et al. 2001

Journal of Biological Chemistry

105

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“…The use of a specific anti-CD86-blocking Ab and the NK cell lines NK92 and YTS further confirmed the involvement of CD86, but not CD80, in triggering NK cell-mediated cytotoxicity of porcine cells. To investigate the combinatorial role of CD86 and the carbohydrate epitope Gal␣1,3-Gal on NK cell activation, we expressed hCD152-hCD59 in PAEC and fibroblasts derived from our H transferase (HT)-transgenic pigs (35). HT down-regulates Gal␣1,3-Gal Ag expression and generates fucosylated residues (H-Ag, the O blood group Ag) that are universally tolerated in humans (35,36).…”

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confidence: 99%

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Costa

Barber

Fodor

2002

The Journal of Immunology

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Delayed xenograft rejection is a major hurdle that needs to be addressed to prolong graft survival in pig-to-primate xenotransplantation. NK cell activation has been implicated in delayed xenograft rejection. Both Ab-dependent and independent mechanisms are responsible for the high susceptibility of porcine cells to human NK cell-mediated cytotoxicity. Previous reports demonstrated a role of Galα1,3-Gal Ag in triggering the Ab-independent responses. We hypothesize that expression of CD80 and/or CD86 on porcine cells may also play a role in NK cell activation as human NK cells express a variant of CD28. Our initial analysis showed that porcine endothelial cells and fibroblasts express CD86, but not CD80. Genetic engineering of these cells to express hCD152-hCD59, a chimeric molecule designed to block CD86 in cis, was accompanied by a reduction in susceptibility to human NK cell-mediated cytotoxicity. The use of a specific anti-porcine CD86-blocking Ab and the NK92 and YTS cell lines further confirmed the involvement of CD86 in triggering NK cell-mediated lysis of porcine cells. Maximal protection was achieved when hCD152-hCD59 was expressed in H transferase-transgenic cells, which show reduced Galα1,3-Gal expression. In this work, we describe two mechanisms of human NK cell-mediated rejection of porcine cells and demonstrate that genetically modified cells resist Ab-independent NK cell-mediated cytotoxicity.

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“…1 Distribución de los genes del sistema HLA Clase I, II y III organismo, son la parte fundamental de la respuesta inmunitaria en el reconocimiento de proteínas antigénicas y en el humano se denomina a este sistema HLA (Human leukocyte antigen) (4,(11)(12)(13)(14), Figura 1.…”

Section: Introductionunclassified

Del alotransplante al xenotransplante: la compatibilidad antigénica donante-receptor por medio del Complejo Mayor de Histocompatibilidad CMH

Amaya

Navarrete

2006

nova

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ResumenLos transplantes de órganos han sido una herramienta del área clínica para la búsqueda del mejoramiento de la calidad en la salud humana e igualmente brinda al paciente una nueva oportunidad de vida. Esta solución se ha visto obstaculizada por el déficit de órganos suficientes ya que para su obtención se han encontrado grandes dificultades, dentro de las cuales se pueden nombrar la negativa de las familias, los costos, la demora en la captación del órgano, la falta de infraestructura logística que permita realizarlo en un tiempo óptimo, las fallas en el transporte del órgano poniendo en riesgo el éxito del transplante, entre otras. Por todo lo anterior y teniendo en cuenta el posible rechazo a causa de la compatibilidad de los complejos reconocedores de antígeno entre donante y receptor, se ha fijado la mirada en órganos de animales denominados xenogénicos que puedan suplir esta problemática y nos permita tener una alternativa fácil de obtención de órganos para las personas que así lo requieran. Esta publicación tiene como objeto realizar una revisión amplia de las temáticas relacionadas con el transplante, con el fin de analizar desde el punto de vista molecular e inmunológico las ventajas y desventajas de un transplante xenogénico.Palabras claves: alogénico, complejo mayor de histocompatibilidad (CMH), histocompatibilidad, linfocitos T, polimorfismo, xenotransplante. AbstractOrgan transplants have been a clinical area tool for the search of the improvement of the quality in the human health and it also offers the patient a new opportunity of life. This solution has been blocked by the deficit of enough organs. To obtain them there have been big difficulties like the negative of the families, the costs, the delay in the reception of the organ, the lack of logistical infrastructure that allows to carry it in a timely fashion, the flaws in the transport of the organ risking the success of the transplant, among others. For all the above and keeping in mind the possible rejection because of the compatibility of the complex antigen to recognize among donor and receiver, the scientists have looked at organs of animals denominated xenogenics that can solve this problem and it will allow us to have an alternative for the easy obtaining of organs for people that require it. This publication tries to carry out a wide revision of the contents of the transplant with the purpose of analyzing the advantages and disadvantages of a xenogenic transplant from the molecular and immunologic point of view. ARTÍCULO DE REVISIÓN

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Expression of the human α:1,2‐fucosyltransferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum‐mediated cytolysis

Cited by 86 publications

References 60 publications

Remodeling of the Major Pig Xenoantigen by N-Acetylglucosaminyltransferase III in Transgenic Pig

Remodeling of the Major Pig Xenoantigen by N-Acetylglucosaminyltransferase III in Transgenic Pig

Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Galα1,3-Gal Is Inhibited in Genetically Modified Porcine Cells

Del alotransplante al xenotransplante: la compatibilidad antigénica donante-receptor por medio del Complejo Mayor de Histocompatibilidad CMH

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