期刊
MOLECULAR THERAPY
卷 27, 期 9, 页码 1586-1596出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2019.05.022
关键词
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资金
- Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI)
- National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the NIH
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006008, ZIAHL002339, ZIAHL002338] Funding Source: NIH RePORTER
Busulfan conditioning is utilized for hematopoietic stem cell (HSC) depletion in the context of HSC gene-therapy conditioning but may result in insufficient immunosuppression. In this study, we evaluated whether additional immunosuppression is required for efficient engraftment of gene-modified cells using a rhesus HSC lentiviral gene-therapy model. We transduced half of rhesus CD34(+) cells with an enhanced green fluorescent protein (GFP)-encoding vector (immunogenic) and the other half with a gamma-globin-encoding vector (no predicted immunogenicity). After autologous transplantation of both transduced cell populations following myeloablative busulfan conditioning (5.5 mg/kg/day for 4 days), we observed immunological rejection of GFP-transduced cells up to 3 months post-transplant and stable engraftment of gamma-globin-transduced cells in two animals, demonstrating that ablative busulfan conditioning is sufficient for engraftment of gene-modified cells producing non-immunogenic proteins but insufficient to permit engraftment of immunogenic proteins. We then added immunosuppression with abatacept and sirolimus to busulfan conditioning and observed engraftment of both GFP-and gamma-globin-transduced cells in two animals, demonstrating that additional immunosuppression allows for engraftment of gene-modified cells expressing immunogenic proteins. In conclusion, myeloablative busulfan conditioning should permit engraftment of gene-modified cells producing non-immunogenic proteins, while additional immunosuppression is required to prevent immunological rejection of a neoantigen.
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