期刊
BLOOD
卷 122, 期 8, 页码 1341-1349出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-03-478255
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资金
- Cancer Center [CA16672, CA124782, CA120956, CA141303, CA116127, CA148600]
- Burroughs Wellcome Fund
- Cancer Prevention and Research Institute of Texas
- Caryn Papantonakis
- CLL Global Research Foundation
- DARPA (Defense Sciences Office)
- Department of Defense
- Estate of Noelan L. Bibler
- Gillson Longenbaugh Foundation
- Harry T. Mangurian, Jr, Fund for Leukemia Immunotherapy
- Institute of Personalized Cancer Therapy
- Leukemia and Lymphoma Society
- Lymphoma Research Foundation
- MD Anderson Cancer Center's Sister Institution Network Fund
- Miller Foundation
- Mr Herb Simons
- Mr and Mrs Joe H. Scales
- Mr and Mrs Rick Calhoon
- Mr Thomas Scott
- Mr Thomas Scott
- National Foundation for Cancer Research
- Paula Gavrel Asher Foundation
- Pediatric Cancer Research Foundation
- Robert J. Kleberg, Jr and Helen C. Kleberg Foundation
- Uehara Memorial Foundation
- William Lawrence and Blanche Hughes Children's Foundation
- National Institutes of Health [CA084198, CA087869, HD045022]
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 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 natural killer cells of cells that had lost HLA expression was circumvented by enforced expression of nonclassical HLA molecules. Furthermore, we demonstrate that zinc finger nucleases 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 a single donor can be administered to multiple recipients.
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