| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
-1,3-Galactose Expression on Porcine Endothelial Cells Prevents Complement-Induced Lysis but Not Direct Xenogeneic NK Cytotoxicity1
* Department of Internal Medicine, Laboratory for Transplantation Immunology, University Hospital, Zurich, Switzerland;
Immerge Biotherapeutics, Cambridge, MA 02139; and
Cardiology, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland
The galactose-
-1,3-galactose (Gal) carbohydrate epitope is expressed on porcine, but not human cells, and therefore represents a major target for preformed human anti-pig natural Abs (NAb). Based on results from pig-to-primate animal models, NAb binding to porcine endothelial cells will likely induce complement activation, lysis, and hyperacute rejection in pig-to-human xenotransplantation. Human NK cells may also contribute to innate immune responses against xenografts, either by direct recognition of activating molecules on target cells or by Fc
RIII-mediated xenogeneic Ab-dependent cellular cytotoxicity (ADCC). The present study addressed the question as to whether the lack of Gal protects porcine endothelial cells from NAb/complement-induced lysis, direct xenogeneic NK lysis, NAb-dependent ADCC, and adhesion of human NK cells under shear stress. Homologous recombination, panning, and limiting dilution cloning were used to generate an Gal-negative porcine endothelial cell line, PED2*3.51. NAb/complement-induced xenogeneic lysis of PED2*3.51 was reduced by an average of 86% compared with the Gal-positive phenotype. PED2*3.51 resisted NK cell-mediated ADCC with a reduction of lysis ranging from 30 to 70%. However, direct xenogeneic lysis of PED2*3.51, mediated either by freshly isolated or IL-2-activated human NK cells or the NK cell line NK92, was not reduced. Furthermore, adhesion of IL-2-activated human NK cells did not rely on Gal expression. In conclusion, removal of Gal leads to a clear reduction in complement-induced lysis and ADCC, but does not resolve adhesion of NK cells and direct anti-porcine NK cytotoxicity, indicating that Gal is not a dominant target for direct human NK cytotoxicity against porcine cells.
This article has been cited by other articles:
|
|
 |
|
  M. Saethre, M. K. J. Schneider, J. D. Lambris, P. Magotti, G. Haraldsen, J. D. Seebach, and T. E. Mollnes Cytokine Secretion Depends on Gal{alpha}(1,3)Gal Expression in a Pig-to-Human Whole Blood Model J. Immunol., May 1, 2008; 180(9): 6346 - 6353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. R. Rossi, M. R. Mautino, R. C. Unfer, T. M. Seregina, N. Vahanian, and C. J. Link Effective Treatment of Preexisting Melanoma with Whole Cell Vaccines Expressing {alpha}(1,3)-Galactosyl Epitopes Cancer Res., November 15, 2005; 65(22): 10555 - 10561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Forte, B. G. Lilienfeld, B. C. Baumann, and J. D. Seebach Human NK Cytotoxicity against Porcine Cells Is Triggered by NKp44 and NKG2D J. Immunol., October 15, 2005; 175(8): 5463 - 5470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Liu, L. Xu, F. Yang, D. Li, F. Gong, and T. Xu Rapid biogenesis and sensitization of secretory lysosomes in NK cells mediated by target-cell recognition PNAS, January 4, 2005; 102(1): 123 - 127. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
