Genetically modified HLA class I molecules able to inhibit human NK cells without provoking alloreactive CD8+ CTLs.
Human NK cells are likely to be important effectors of xenograft rejection. Expression of HLA class I molecules by transfected porcine cells can protect them from human NK cell-mediated lysis; however, this strategy has the potential to augment the anti-graft response by recipient CD8(+) T cells recognizing foreign pig peptides presented by HLA. In this study we show that the introduction of a mutation (D227K) in the alpha(3) domain of HLA-Cw3 abrogates its recognition by CD8-dependent T cells but leaves intact its ability to function as an inhibitory ligand for NK cells. Such genetically modified molecules may have potential therapeutic applications in the prevention of delayed xenograft rejection and in the facilitation of allogeneic and xenogeneic bone marrow engraftment.
Sharland
Alexandra
A
Laboratory of Molecular and Cellular Immunology, Transplantation Biology Research Center, Boston, MA 02129, USA.
Patel
Amy
A
Lee
Josie Han
JH
Cestra
Aimee E
AE
Saidman
Susan
S
Waneck
Gerald L
GL
D001224:Aspartic Acid / Q000235:genetics; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed / Q000276:immunology / Q000378:metabolism; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000235:genetics* / Q000276:immunology*; D005822:Genetic Vectors / Q000276:immunology / Q000378:metabolism; D015236:HLA-C Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D016131:Lymphocyte Subsets / Q000276:immunology; D008239:Lysine / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D011971:Receptors, Immunologic / Q000378:metabolism; D054340:Receptors, KIR; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D001224:Aspartic Acid; D008239:Lysine