Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy.
Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy.
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DOI：
10.1371/journal.pone.0065519
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jensen MC
中科院分区：
文献类型：
--
作者：
Jonnalagadda M;Brown CE;Chang WC;Ostberg JR;Forman SJ;Jensen MC
Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped. Here, we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate (MTX) and mycophenolate mofetil (MMF) in a multicistronic lentiviral vector for in vivo T lymphocyte selection. We found that co-expression of human dihydrofolate reductase (DHFRFS; L22F, F31S) and inosine monophosphate dehydrogenase II (IMPDH2IY; T333I, S351Y) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically (up to 0.1 µM MTX and 1.0 µM MPA). Furthermore, using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells, in vivo selection studies demonstrate that huEGFRt+DHFRFS+IMPDH2IY+ T cells could be enriched following adoptive transfer either by systemic administration of MTX alone (4.4 -fold), MMF alone (2.9-fold), or combined MTX and MMF (4.9-fold). These findings demonstrate the utility of both DHFRFS/MTX and IMPDH2IY/MMF for in vivo selection of lentivirally transduced human T cells. Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients.
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影响因子：
15.9
作者：
Berger, Carolina;Jensen, Michael C.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
病毒特异性的T细胞设计为共表达肿瘤特异性受体：神经母细胞瘤个体中的持久性和抗肿瘤活性。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.2
作者：
Gatlin, J;Douglas, J;Garcia, V
通讯作者：
Garcia, V
影响因子：
82.9
作者：
Riddell, SR;Elliott, M;Greenberg, PD
通讯作者：
Greenberg, PD
影响因子：
20.3
作者：
Berger, C;Flowers, ME;Riddell, SR
通讯作者：
Riddell, SR