HLA-Cw3 expression on porcine endothelial cells protects against xenogeneic cytotoxicity mediated by a subset of human NK cells.
There is increasing evidence that NK cells make an important contribution to human anti-porcine xenogeneic cytotoxicity. Most allogeneic as well as autologous normal cells are not susceptible to NK cell-mediated cytotoxicity because they express inhibitory molecules encoded within the MHC class I loci. The protective signal is delivered to NK cells through killer cell-inhibitory receptors expressing different MHC class I specificities. It has been proposed that xenogeneic target cells may be susceptible to NK cell-mediated lysis because their MHC class I molecules fail to be recognized by human killer cell-inhibitory receptors. To explore this hypothesis, we examined the effect of human MHC class I expression on porcine target cell lysis by human NK cells. An immortalized porcine bone marrow-derived endothelial cell line (2A2) was transfected with three different human MHC class I allelic genes (HLA-A2, -B27, or -Cw3). The cytotoxic activity of several GL183+ NK clones, which lysed untransfected porcine cells effectively, was substantially blocked by the presence of HLA-Cw3. In contrast, HLA-Cw3-positive cells were not protected against lysis by GL183- EB6+ NK clones. The expression of HLA-B27 or HLA-A2 molecules on pig target cells did not provide substantial protection from lysis by any of the NK clones tested. In addition to confirming the hypothetical basis of NK cell-mediated killing of xenogeneic targets, these results have practical implications as an approach to overcoming NK cell-mediated cytotoxicity, which may be an obstacle to pig-to-human xenotransplantation.
Seebach
J D
JD
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA. Seebach.Joerg@mgh.harvard.edu
Comrack
C
C
Germana
S
S
LeGuern
C
C
Sachs
D H
DH
DerSimonian
H
H
D000818:Animals; D015478:Antigens, Heterophile / Q000096:biosynthesis / Q000276:immunology*; D000954:Antigens, Surface / Q000096:biosynthesis; D001854:Bone Marrow Cells; D002461:Cell Line, Transformed; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D004727:Endothelium / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015236:HLA-C Antigens / Q000096:biosynthesis*; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000145:classification / Q000276:immunology*; D013552:Swine / Q000276:immunology; D014162:Transfection / Q000276:immunology
D015478:Antigens, Heterophile; D000954:Antigens, Surface; D015236:HLA-C Antigens; C038653:HLA-C*03 antigen