Recent investigations into pig antigen and anti-pig antibody expression

Byrne, Guerard W.; McGregor, Christopher G.A.; Breimer, Michael E.

doi:10.1016/j.ijsu.2015.07.724

Cited by 66 publications

(40 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gal is not expressed in humans or Old World NHPs but is expressed at high levels in porcine tissues. Genetically modified pigs, with a mutation in the GGTA‐1 locus (GTKO), do not express the Gal antigen . The introduction of GTKO donor organs eliminated anti‐Gal‐mediated xenograft rejection, but did not eliminate antibody‐mediated rejection and instead highlighted the importance of antibody directed to non‐Gal pig antigens …”

Section: Introductionmentioning

confidence: 99%

B4GALNT2 and xenotransplantation: A newly appreciated xenogeneic antigen

Byrne

Ahmad-Villiers

et al. 2018

Xenotransplantation

View full text Add to dashboard Cite

Analysis of non-Gal antibody induced after pig-to-baboon cardiac xenotransplantation identified the glycan produced by porcine beta-1,4-N-acetyl-galactosaminyltransferase 2 (B4GALNT2) as an immunogenic xenotransplantation antigen. The porcine B4GALNT2 enzyme is homologous to the human enzyme, which synthesizes the human SDa blood group antigen. Most humans produce low levels of anti-SDa IgM which polyagglutinates red blood cells from rare individuals with high levels of SDa expression. The SDa glycan is also present on GM2 gangliosides. Clinical GM2 vaccination studies for melanoma patients suggest that a human antibody response to SDa can be induced. Expression of porcine B4GALNT2 in human HEK293 cells results in increased binding of anti-SDa antibody, and increased binding of Dolichos biflorus agglutinin (DBA) a lectin commonly used to detect SDa. In pigs, B4GALNT2 is expressed by vascular endothelial cells and endothelial cells from a wide variety of pig backgrounds stain with DBA suggesting that porcine vascular expression of B4GALNT2 is not polymorphic. Mutations in B4GALNT2 have been engineered in mice and pigs. In both species, the B4GALNT2-KO animals are apparently normal and no longer show evidence of SDa antigen expression. Pig tissues with a mutation in B4GALNT2, added to a background of alpha-1,3-galactosyltransferase deficient (GGTA1-KO) and cytidine monophosphate-N-acetylneuraminic acid hydroxylase deficient (CMAH-KO), show reduced antibody binding, confirming the presence of B4GALNT2 dependent antibodies in both humans and nonhuman primates. Preclinical xenotransplantation using B4GALNT2 deficient donors has recently been reported. Elimination of this source of immunogenic pig antigen should minimize acute injury by preformed anti-pig antibody and eliminate an induced clinical immune response to this newly appreciated xenotransplantation antigen.

show abstract

Section: Introductionmentioning

confidence: 99%

B4GALNT2 and xenotransplantation: A newly appreciated xenogeneic antigen

Byrne

Ahmad-Villiers

et al. 2018

Xenotransplantation

View full text Add to dashboard Cite

show abstract

“…Other genetic modifications of source pigs with potential beneficial effects include the removal of the additional 2 known xenoantigens, (I) N-glycolylneuraminc acid, ie, knockout of the cytidine monophosphate-N-acetylneuraminic acid hydroxylase gene CMAH 61 and (ii) the Sd(a) antigen, ie, knockout of the β1,4N-acetylgalactosaminyltransferase gene (β 4GALNT2 ) 62 (reviewed in 63 ). Human antibody binding to pig cells not expressing these 3 antigens is greatly reduced.…”

Section: Other Potential Genetic Modifications Of Islet-source Pigsmentioning

confidence: 99%

Progress in Clinical Encapsulated Islet Xenotransplantation

et al. 2016

View full text Add to dashboard Cite

At the 2015 combined congress of the CTS, IPITA, and IXA, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics – (i) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (ii) the inflammatory response to encapsulated pig islets, (iii) methods to improve the secretion of insulin by pig islets, (iv) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (v) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (i) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (ii) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (iii) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (iv) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic-engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally-harmonized ethical and regulatory framework.

show abstract

“…Other genetic modifications of donor pigs with putative beneficial effects on the outcome of islet xenotransplantation include the removal of additional xenoantigens, such as Neu5Gc (knockout of the cytidine monophosphate-Nacetylneuraminic acid hydroxylase gene CMAH) and Sd(a), (knockout of the beta-1, 4-N-acetyl-galactosaminyl transferase 2 gene B4GALNT2) (reviewed in [76]). Preliminary in vitro studies indicated that elimination of Neu5Gc in addition to αGal may reduce early pig islet loss from IBMIR [77].…”

Section: Genetic Modification Of Islets Donor Pigsmentioning

confidence: 99%

Current Concepts of Using Pigs as a Source for Beta-Cell Replacement Therapy of Type 1 Diabetes

et al. 2016

View full text Add to dashboard Cite

The global prevalence of insulin-dependent diabetes mellitus is rapidly increasing. In spite of major improvements in insulin treatment regimens and diabetes technology (e.g., artificial pancreas devices), glucose control remains problematic in a substantial proportion of diabetic patients. Those patients may benefit from beta-cell replacement therapies. Allotransplantation of pancreas or isolated pancreatic islets is limited by the small number of organ donors. Thus, alternative sources of beta-cells are being developed and tested. These include endocrine progenitor cells or mature beta-cells derived from pluripotent human stem cells and attempts to derive human pancreas tissue in animal hosts by interspecific chimeric complementation experiments. Xenotransplantation of porcine islets is a realistic alternative option. Immune rejection of xenoislets can be prevented by immunosuppression of the recipient or by encapsulation of the islets in microdevices or macrodevices. Using precise and efficient genetic engineering of donor pigs, immune-protected xenoislets with improved functionality can be generated.

show abstract

Recent investigations into pig antigen and anti-pig antibody expression

Cited by 66 publications

References 53 publications

B4GALNT2 and xenotransplantation: A newly appreciated xenogeneic antigen

B4GALNT2 and xenotransplantation: A newly appreciated xenogeneic antigen

Progress in Clinical Encapsulated Islet Xenotransplantation

Current Concepts of Using Pigs as a Source for Beta-Cell Replacement Therapy of Type 1 Diabetes

Contact Info

Product

Resources

About