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Immune responses to alpha1,3 galactosyltransferase knockout pigs
Gisella Puga Yung1, Mårten K J Schneider, Jörg D Seebach
1Service of Clinical Immunology and Allergology, Department of Internal Medicine, University Hospital and Medical Faculty, Geneva, Switzerland.
Current Opinion in Organ Transplantation
|March 21, 2009
Summary
Genetically modified pigs lacking alpha1,3-galactosyltransferase (GalT-KO) show negligible Gal expression, reducing but not eliminating immune responses. New research identifies non-Gal antigens and cellular responses crucial for xenograft survival.
Area of Science:
- Immunology
- Xenotransplantation
- Genetics
Background:
- The primary barrier to xenotransplantation is the hyperacute immune rejection mediated by pre-existing antibodies against carbohydrate antigens, particularly alpha-galactosyl epitopes (Gal).
- Generation of alpha1,3-galactosyltransferase knockout (GalT-KO) pigs aims to eliminate Gal expression and mitigate this rejection.
- However, residual immune responses and the role of non-Gal antigens require further investigation.
Purpose of the Study:
- To review the current understanding of the immune response to GalT-KO pig xenografts.
- To investigate remaining Gal epitopes, non-Gal xenoantigens, and cellular responses against GalT-KO tissues.
Main Methods:
- Review of current literature on GalT-KO pigs and xenotransplantation immunology.
- Analysis of findings related to Gal epitope expression in GalT-KO pigs.
- Examination of anti-non-Gal antibody responses and cellular interactions with GalT-KO cells.
Main Results:
- GalT-KO pigs express negligible levels of Gal, with no detectable isoglobotrihexosylceramide 3.
- Anti-non-Gal antibodies target several porcine carbohydrate xenoantigens.
- GalT-KO pig endothelial cells do not induce cytokine secretion or E-selectin upregulation upon co-culture with human blood, unlike wildtype cells. Gal does not regulate human leukocyte transmigration across porcine endothelium.
Conclusions:
- Elimination of Gal in GalT-KO pigs presents new immunological challenges, including the development of anti-non-Gal antibodies and the identification of their targets.
- Cellular immune components such as neutrophils, macrophages, NK cells, and T cells remain critical in the xenograft response.
- Further research is needed to fully characterize and overcome these non-Gal mediated immune responses for successful xenotransplantation.
