Immune responses to α1,3 galactosyltransferase knockout pigs

Yung, Gisella Puga; Schneider, Mårten K J

doi:10.1097/mot.0b013e328329250d

Cited by 29 publications

(9 citation statements)

References 54 publications

(51 reference statements)

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“…This Ag is characterized by a terminal N -glycolylneuraminic acid (Neu5Gc) generated by conversion of the activated sugar donor CMP-Neu5Ac into CMP-Neu5Gc by cytidine monophosphate- N -acetylneuraminic acid hydroxylase (CMAH) [ 87 – 90 ]. Furthermore, an uncharacterized saccharide on pEC and synthesized by the porcine enzyme beta1,4 N -acetylgalactosaminyltransferase (B4GALNT2) is recognized by human XenoAbs [ 33 ]. The expression of Neu5Gc and lack of the corresponding natural XenoAbs in NHP, and the fact that deletion of CMAH in GalT-KO pigs increases NHP antibody binding, renders the interpretation of results obtained in pig-to-NHP models difficult [ 89 , 91 ].…”

Section: Recognition and Destruction Of Pig Endothelium By Human Nmentioning

confidence: 99%

The Role of NK Cells in Pig-to-Human Xenotransplantation

Yung

Schneider

2017

Journal of Immunology Research

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Recruitment of human NK cells to porcine tissues has been demonstrated in pig organs perfused ex vivo with human blood in the early 1990s. Subsequently, the molecular mechanisms leading to adhesion and cytotoxicity in human NK cell-porcine endothelial cell (pEC) interactions have been elucidated in vitro to identify targets for therapeutic interventions. Specific molecular strategies to overcome human anti-pig NK cell responses include (1) blocking of the molecular events leading to recruitment (chemotaxis, adhesion, and transmigration), (2) expression of human MHC class I molecules on pECs that inhibit NK cells, and (3) elimination or blocking of pig ligands for activating human NK receptors. The potential of cell-based strategies including tolerogenic dendritic cells (DC) and regulatory T cells (Treg) and the latest progress using transgenic pigs genetically modified to reduce xenogeneic NK cell responses are discussed. Finally, we present the status of phenotypic and functional characterization of nonhuman primate (NHP) NK cells, essential for studying their role in xenograft rejection using preclinical pig-to-NHP models, and summarize key advances and important perspectives for future research.

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Section: Recognition and Destruction Of Pig Endothelium By Human Nmentioning

confidence: 99%

The Role of NK Cells in Pig-to-Human Xenotransplantation

Yung

Schneider

2017

Journal of Immunology Research

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“…Although hyperacute rejection can be prevented, the next rejection phenomenon unique to xenotransplantation, known as delayed xenograft rejection or acute vascular rejection, will occur ( 60 ). In addition, new immunological problems arise, for example, except the α-Gal epitope, there exist non-gal carbohydrate antigens and the identification of their elusive antigens as neutrophils, macrophages, natural killer cells and T cells ( 61 ).…”

Section: Clinical Exploitationmentioning

confidence: 99%

Characteristics of α-Gal epitope, anti-Gal antibody, α1,3 galactosyltransferase and its clinical exploitation (Review)

Huai

Pan

Yang

et al. 2015

International Journal of Molecular Medicine

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The α-Gal epitope (Galα1,3Galα1,4GlcNAc-R) is ubiquitously presented in non-primate mammals, marsupials and New World Monkeys, but it is absent in humans, apes and Old World monkeys. However, the anti-Gal antibody (~1% of immunoglobulins) is naturally generated in human, and is found as the immunoglobulin G (IgG), IgM and IgA isotypes. Owing to the specific binding of the anti-Gal antibody with the α-Gal epitope, humans have a distinct anti-α-gal reactivity, which is responsible for hyperacute rejection of organs transplanted from α-gal donors. In addition, the α1,3 galactosyltransferases (α1,3GT) can catalyze the synthesis of the α-Gal epitope. Therefore, the α1,3GT gene, which encodes the α1,3GT, is developed profoundly. The distributions of the α-Gal epitope and anti-Gal antibody, and the activation of α1,3GT, reveal that the enzyme of α1,3GT in ancestral primates is ineffective. Comparison of the nucleotide sequence of the human α1,3-GT pseudogene to the corresponding different species sequence, and according to the evolutionary tree of different species, the results of evolutionary inactivation of the α1,3GT gene in ancestral primates attribute to the mutations under a stronger selective pressure. However, on the basis of the structure, the mechanism and the specificity of the α-Gal epitope and anti-Gal antibody, they can be applied to clinical exploitation. Knocking out the α1,3GT gene will eliminate the xenoantigen, Gal(α1,3)Gal, so that the transplantation of α1,3GT gene knockout pig organ into human becomes a potential clinically acceptable treatment for solving the problem of organ shortage. By contrast, the α-Gal epitope expressed through the application of chemical, biochemical and genetic engineering can be exploited for the clinical use. Targeting anti-Gal-mediated autologous tumor vaccines, which express α-Gal epitope to antigen-presenting cells, would increase their immunogenicity and elicit an immune response, which will be potent enough to eradicate the residual tumor cells. For tumor vaccines, the way of increasing immunogenicity of certain viral vaccines, including flu vaccines and human immunodeficiency virus vaccines, can also be used in the elderly. Recently, α-Gal epitope nanoparticles have been applied to accelerate wound healing and further directions on regeneration of internally injured tissues.

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“…It seems reasonable to postulate that elimination of the GGTA1 transferase in pigs removes all Galα3‐terminating carbohydrate antigens, and it seems fairly secure to postulate that even if a minimal number of Gal antigens (such as iGb3) should remain in GalT‐KO pig tissue, this will not curse antibody‐mediated cell damage. However, Seebach and co‐workers [34] have pointed out the possibility of cellular xenogeneic reaction mediated by iGb3.…”

Section: Carbohydrate Antigen Profile In Galt‐ko Pigsmentioning

confidence: 99%

Gal/non‐Gal antigens in pig tissues and human non‐Gal antibodies in the GalT‐KO era¹

Breimer

2011

Xenotransplantation

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Our knowledge regarding Gal and non-Gal antigens in GalT-KO pig tissues can be summarized as α3Galactosyl-tranferase gene knock out eliminates the Galα3Galβ4GlcNAc-R antigen expression in pig tissues as well as anti-Gal antibody binding. Other Galα-terminating saccharides (e.g. iGb3 glycolipids and Galα2 determinants) may be present but have not been documented. α3Galactosyl-tranferase gene knock out slightly changes the carbohydrate antigen expression but no "new" antigens recognized by the human immune system have been found. Non-Gal antigens are both of protein and carbohydrate nature but their exact chemical structures are poorly defined. Regarding human non-Gal antibodies our knowledge is as Non-Gal antibodies exist naturally and increase in humans/non-human primate (NHP) receiving WT or GalT-KO pig grafts. Non-Gal antibodies with new antigen epitope recognition can be induced in humans/NHP after challenge by WT or GalT-KO pig grafts. Non-Gal antibodies react with both carbohydrates and proteins. Part of the protein reactivity is directed to glycoprotein carbohydrates chains. Non-Gal antibodies reacting with neuraminic acid terminated saccharides (both N-Acetyl and N-Glycoloyl variants) are present in humans/NHP. Anti-neuraminic acid antibodies are increased, as well as induced, after grafting pig organs into humans/NHP. Non-Gal antibodies does not cause hyperacute xenorejection but can be cytotoxic and cause xenoorgan damage. If humans sensitized to HLA antigens are at a higher risk of rejecting pig xenograft compared with non-sensitized individuals is not fully clarified. Clinical trials are needed to evaluate the relevance of non-Gal antigens/antibodies and for the xenofield to advance.

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Immune responses to α1,3 galactosyltransferase knockout pigs

Cited by 29 publications

References 54 publications

The Role of NK Cells in Pig-to-Human Xenotransplantation

The Role of NK Cells in Pig-to-Human Xenotransplantation

Characteristics of α-Gal epitope, anti-Gal antibody, α1,3 galactosyltransferase and its clinical exploitation (Review)

Gal/non‐Gal antigens in pig tissues and human non‐Gal antibodies in the GalT‐KO era¹

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Immune responses to α1,3 galactosyltransferase knockout pigs

Cited by 29 publications

References 54 publications

The Role of NK Cells in Pig-to-Human Xenotransplantation

The Role of NK Cells in Pig-to-Human Xenotransplantation

Characteristics of α-Gal epitope, anti-Gal antibody, α1,3 galactosyltransferase and its clinical exploitation (Review)

Gal/non‐Gal antigens in pig tissues and human non‐Gal antibodies in the GalT‐KO era1

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Gal/non‐Gal antigens in pig tissues and human non‐Gal antibodies in the GalT‐KO era¹