from allogeneic donors Towards eliminating HLA class I expression to generate universal cells
2013
ABSTRACT Long-term engraftment of allogeneic cells necessitates eluding immune-mediated rejection which is currently achieved by matching for human leukocyte antigen (HLA) expression, immunosuppression, and/or delivery of donor-derived cells to sanctuary sites. Genetic engineering provides an alternative approach to avoid clearance of cells that are recognized as “non-self” by the recipient. To this end, we developed designer zinc finger nucleases (ZFNs) and employed a “hit-and-run” approach to genetic editing for selective elimination of HLA expression. Electro-transfer of mRNA species coding for these engineered nucleases completely disrupted expression of HLA-A on human T-cells, including CD19-specific T-cells. The HLA-A neg T-cell pools can be enriched and evade lysis by HLA-restricted cytotoxic T-cell clones. Recognition by NK-cells of cells that had lost HLA expression was circumvented by enforced expression of non-classical HLA molecules. Furthermore, we demonstrate that ZFNs can eliminate HLA-A expression from embryonic stem cells which broadens the applicability of this strategy beyond infusing HLA-disparate immune cells. These findings establish that clinically-appealing cell types derived from donors with disparate HLA expression can be genetically edited to evade an immune response and provide a foundation whereby cells from one donor can be administered to multiple recipients. From bloodjournal.hematologylibrary.org at M D ANDERSON HOSP on June 10, 2013. For personal use only.
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