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Genetically Modified HLA Class I Molecules Able to Inhibit Human NK Cells Without Provoking Alloreactive CD8⁺ CTLs¹

Alexandra Sharland^*, Amy Patel^*, Josie Han Lee^*, Aimee E. Cestra^*, Susan Saidman and Gerald L. Waneck^2,*

^* Laboratory of Molecular and Cellular Immunology, Transplantation Biology Research Center, and Histocompatability Laboratory, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129

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 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.

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